The Open Leukemia Journal




(Discontinued)

ISSN: 1876-8164 ― Volume 5, 2013

The Common Leukemic Fusions in Pathogenesis and in Treatment Response in Acute Myeloid Leukemia



Temesgen Fufan, Shafqat Ahmed , Jenny L Persson*
Division of Experimental Cancer Research, Department of Laboratory Medicine, Clinical Research Center in Malmö, Lund University, 205 02, Malmö, Sweden

Abstract

Chromosomal abnormalities are the most common alterations in acute myeloid leukemia (AML). Among those abnormalities, chromosomal translocations that produce the oncogenic fusion proteins have been frequently observed in different subtypes of AML. Although molecular mechanisms underlying the consequences of the oncogenic transformation resulted from the fusion proteins have been extensively studied, little is known about the molecular events cooperative with the oncogenic fusion proteins in the pathogenesis of leukemia and the cellular mechanisms with regard to the predictive roles of the fusions in treatment response. In this article, we will present an overview of the important aspects of AML-associated fusion proteins and their regulated transcriptional networks in pathogenesis and prognosis of AML. We will also discuss the recent findings pertaining to the functional link between the oncogenic fusions and response of leukemic cells to the treatment. Understanding the regulation of AML-associated fusions and their association with disease characteristics, patient outcome and treatment response will be of fundamental importance for predicting the effectiveness of the treatment and design the specific therapeutic strategies.

Keywords: Acute myeloid leukemia, chromosome translocations, leukemic fusion proteins, transcriptional factors, treatment response.


Article Information


Identifiers and Pagination:

Year: 2010
Volume: 3
First Page: 1
Last Page: 8
Publisher Id: TOLEUKEMIAJ-3-1
DOI: 10.2174/1876816401003010001

Article History:

Received Date: 7/7/2009
Revision Received Date: 19/10/2009
Acceptance Date: 23/10/2009
Electronic publication date: 7/1/2010
Collection year: 2010

© Fufan et al.; Licensee Bentham Open.

open-access license: This is an open access article licensed under the terms of the Creative Commons Attribution Non-Commercial License (http: //creativecommons.org/licenses/by-nc/3.0/ which permits unrestricted, non-commercial use, distribution and reproduction in any medium, provided the work is properly cited.


* Address correspondence to this author at the Clinical Research Cancer, Division of Experimental Cancer Research, Lund University, Malmö University Hospital, 205 02, Malmö, Sweden; Tel: +46-40-391106; Fax: +46-40-391222; E-mail: jenny_l.persson@med.lu.se





INTRODUCTION

Hematopoiesis is a complicated multistage process that involves the differentiation and maturation of different blood cell types. Thus, to terminally differentiate and mature, cells have to pass through hierarchy of successive developmental stages [1Lutz PG, Moog-Lutz C, Cayre YE. Signaling revisited in acute promyelocytic leukemia Leukemia 2002; 16: 1933-9., 2Speck NA, Gilliland DG. Core-binding factors in haematopoiesis and leukaemia Nat Rev Cancer 2002; 2: 502-13.]. In each stage, the regulatory genes for hematopoiesis are either activated or silenced in a cell type-specific or lineage-specific manner to ensure a precise fine-tuning of the process [3Skalnik DG. Transcriptional mechanisms regulating myeloid-specific genes Gene 2002; 284: 1-21.-7Look AT. Oncogenic transcription factors in the human acute leukemias Science 1997; 278: 1059-64.]. The disruption of this regulatory process may result in different types of blood disorders. Acute myeloid leukemia (AML) is one of the major blood disorders that are associated with disruption of the regulatory processes.

AML is characterized by accumulation of cells at the early stages of the differentiation process [8Wildonger J, Mann RS. The t(8,21) translocation converts AML1 into a constitutive transcriptional repressor Development 2005; 132: 2263-72.-10Bruserud O, Gjertsen BT, Huang T. Induction of differentiation and apoptosis- a possible strategy in the treatment of adult acute myelogenous leukemia Oncologist 2000; 5: 454-62.]. This is mostly attributed to dysfunctional regulatory transcription factors, resulting in aberrant gene expression and function [7Look AT. Oncogenic transcription factors in the human acute leukemias Science 1997; 278: 1059-64., 9Barseguian K, Lutterbach B, Hiebert SW, et al. Multiple subnuclear targeting signals of the leukemia-related AML1/ETO and ETO repressor proteins Proc Natl Acad Sci USA 2002; 99: 15434-9.]. Dysfunction of the regulatory transcription factors in turn results in blocking of the passage of cells through a given developmental stage depending on the subtype of the disease [7Look AT. Oncogenic transcription factors in the human acute leukemias Science 1997; 278: 1059-64.]. Thus, AML is a heterogenous disease, which comprises multiple subtypes [11Bacher U, Kern W, Schnittger S, et al. Correlations of morphology according to FAB and WHO classification to cytogenetics in de novo acute myeloid leukemia a study on 2,235 patients Ann Hematol 2005; 84: 785-91., 12Burmeister T, Thiel E. Molecular genetics in acute and chronic leukemias J Cancer Res Clin Oncol 2001; 127: 80-90.]. The subtypes are classified according to the FAB classification system. The subtypes are denoted as M0-M7 [2Speck NA, Gilliland DG. Core-binding factors in haematopoiesis and leukaemia Nat Rev Cancer 2002; 2: 502-13., 4Kurokawa M, Hirai H. Role of AML1/Runx1 in the pathogenesis of hematological malignancies Cancer Sci 2003; 94: 841-6., 10Bruserud O, Gjertsen BT, Huang T. Induction of differentiation and apoptosis- a possible strategy in the treatment of adult acute myelogenous leukemia Oncologist 2000; 5: 454-62., 13Cripe LD. Adult acute leukemia Curr Probl Cancer 1997; 21: 1-64.]. The grouping is made based on the degree of granulocytic maturation (M1, M2, M3) or monocytic differentiation (M4 & M5) or presence of large number of erythroblasts (M6) or magakaryoblasts (M7) [10Bruserud O, Gjertsen BT, Huang T. Induction of differentiation and apoptosis- a possible strategy in the treatment of adult acute myelogenous leukemia Oncologist 2000; 5: 454-62., 13Cripe LD. Adult acute leukemia Curr Probl Cancer 1997; 21: 1-64.]. The individual subtypes of this heterogenous disease can be identified using multiple methods such as cellular morphology, cytochemistry, immunophenotypes and molecular analysis [14McKenna RW. Multifaceted approach to the diagnosis and classification of acute leukemias Clin Chem 2000; 46: 1252-9.]. For instance, in the most common forms of leukemia, acute promyelocytic leukemia (APL), and acute myeloid leukemia, the differentiation process is blocked at a promyelocyte stage [15Kalantry S, Delva L, Gaboli M, et al. Gene rearrangements in the molecular pathogenesis of acute promyelocytic leukemia J Cell Physiol 1997; 173: 288-96.], and early myeloid stage [16Niebuhr B, Fischer M, Täger M, et al. Gatekeeper function of the RUNX1 transcription factor in acute leukemia Blood Cells Mol Dis 2008; 40: 211-8.], respectively. The blocked cells regain a self-renewal capacity and continue to proliferate and overpopulate the bone marrow. The prognosis of leukemia varies in patients depending on ages of the patients. Combination of age, cytogenetics, and white blood cell count (WBC) is a good prognostic factor. Young age tends to be associated with favorable prognosis, while old age is associated with poor prognosis [13Cripe LD. Adult acute leukemia Curr Probl Cancer 1997; 21: 1-64., 17Stone RM, O'Donnell MR, Sekeres MA, et al. Acute myeloid leukemia Hematology (Am Soc Hematol Educ Prog) 2004; 00: 98-117.]. Cytochemical staining for example is helpful in differentiating AML from ALL as well as identifying subtypes of AML [14McKenna RW. Multifaceted approach to the diagnosis and classification of acute leukemias Clin Chem 2000; 46: 1252-9.]. On the other hand, the specific karyotype is age-independent predictor of the treatment outcome. For example, the t(8; 21), inv(16) and t(15; 17) are indicators of favorable prognosis while, deletion or loss of chromosome 5 or 7 or both is associated with poor prognosis [13Cripe LD. Adult acute leukemia Curr Probl Cancer 1997; 21: 1-64.]. Multiple parameters have been taken into consideration for accurate diagnosis and better choice of treatment regimens. Genome-wide studies in search of complex genetic alterations and identification of possible novel markers have provided novel tools for the diagnosis and treatment of AML [16Niebuhr B, Fischer M, Täger M, et al. Gatekeeper function of the RUNX1 transcription factor in acute leukemia Blood Cells Mol Dis 2008; 40: 211-8.].

In AML, the underlying genetic or epigenetic events lead to disruption of this delicate regulatory mechanism affecting multiple cellular processes and regulatory pathways, especially the stage-specific regulations [6Alcalay M, Orleth A, Sebastiani C, et al. Common themes in the pathogenesis of acute myeloid leukemia Oncogene 2001; 20: 5680-94., 16Niebuhr B, Fischer M, Täger M, et al. Gatekeeper function of the RUNX1 transcription factor in acute leukemia Blood Cells Mol Dis 2008; 40: 211-8.]. A large number of diverse translocations have been described. The most frequent are the t(8; 21), t(15; 17), inv(16) which together with their variants, account for approximately 40% of all AMLs [7Look AT. Oncogenic transcription factors in the human acute leukemias Science 1997; 278: 1059-64.]. These translocations produce the AML1/ETO, PML/RARα, CBFCBFα & CBFβ/SMMHC fusion proteins, respectively [18Okuda T, vanDeursen J, Hiebert SW. AML1 the target of multiple chromosomal translocations in human leukemia is essential for normal fetal liver hematopoiesis Cell 1996; 84: 321-0.] and the RARα [15Kalantry S, Delva L, Gaboli M, et al. Gene rearrangements in the molecular pathogenesis of acute promyelocytic leukemia J Cell Physiol 1997; 173: 288-96.]. These transcription factors are among the most important regulatory proteins that contribute to the normal differentiation and maturation of hematopoietic cells.

Great efforts have been made in treating leukemia to improve the clinical remission and disease-free survival. However, it is important to eliminate the unnecessary side effects that are usually associated with chemotherapy treatment and to improve specificity of drugs. Further, it remains to be investigated in detail whether the leukemic fusions are associated with leukemic subtypes and treatment response.

THE AML1

The core binding factors are a small family of transcription factors CBF comprising a DNA binding CBFα subunit and a non-DNA binding CBFβ subunit. The gene encoding CBFα subunit, AML1 (also known as Runx1, CBFA2, and PEBPA2A), together with the gene encoding CBFβ subunit are essential for hematopoiesis and are frequently fused with other genes to produce fusion genes in human leukemias [4Kurokawa M, Hirai H. Role of AML1/Runx1 in the pathogenesis of hematological malignancies Cancer Sci 2003; 94: 841-6., 19Melnick A, Carlile GW, McConnell MJ, et al. AML-1/ETO fusion protein is a dominant negative inhibitor of transcriptional repression by the promyelocytic leukemia zinc finger protein Blood 2000; 96: 3939-47.-23Petrovick MS, Hiebert SW, Friedman AD, et al. Multiple functional domains of AML1 PU1 and C/EBPa synergize with different regions of AML1 Mol Cell Biol 1998; 18: 3915-25.]. The gene for AML1, is located in 21q22, while the gene for CBFβ, is located on 16q22 [4Kurokawa M, Hirai H. Role of AML1/Runx1 in the pathogenesis of hematological malignancies Cancer Sci 2003; 94: 841-6., 24Ma SK, Wan TS, Chan LC. Cytogenetics and molecular genetics of childhood leukemia Hematol Oncol 1999; 17: 91-105., 25Reilly JT. Pathogenesis of acute myeloid leukaemia and inv(16)(p13,q22) a paradigm for understanding leukaemogenesis Br J Haematol 2005; 128: 18-34.-30Adya N, Stacy T, Speck NA, et al. The leukemic protein core binding factor b (CBFb)-smooth-muscle myosin heavy chain sequesters CBF a 2 into cytoskeletal filaments and aggregates Mol Cell Biol 1998; 18: 7432-43.]. AML1 is the part that contains a DNA-binding and a trans-activation domain, while the CBFβ does not contain any known DNA-binding or a trans-activation domain [4Kurokawa M, Hirai H. Role of AML1/Runx1 in the pathogenesis of hematological malignancies Cancer Sci 2003; 94: 841-6., 21Perry C, Eldor A, Soreq H. Runx1/AML1 in leukemia disrupted association with diverse protein partners Leuk Res 2002; 26: 221-8., 26Kundu M, Liu PP. Function of the inv(16) fusion gene CBFb-MYH11 Curr Opin Hematol 2001; 8: 201-5., 31Downing JR. The AML1-ETO chimaeric transcription factor in acute myeloid leukaemia: biology and clinical significance Br J Haematol 1999; 106: 296-308., 32Lukasik SM, Zhang L, Corpora T, et al. Altered affinity of CBF β-SMMHC for Runx1 explains its role in leukemogenesis Nat Struct Biol 2002; 9: 674-9.]. However, it is believed that the CBFβ subunit strengthens the binding of the AML1 [31Downing JR. The AML1-ETO chimaeric transcription factor in acute myeloid leukaemia: biology and clinical significance Br J Haematol 1999; 106: 296-308., 33Asou N. The role of a Runt domain transcription factor AML1/RUNX1 in leukemogenesis and its clinical implications Crit Rev Oncol Hematol 2003; 45: 129-50.]. Furthermore, the CBFβ is believed to stabilize the AML1 by protecting it from ubiquitin-mediated degradation [21Perry C, Eldor A, Soreq H. Runx1/AML1 in leukemia disrupted association with diverse protein partners Leuk Res 2002; 26: 221-8., 33Asou N. The role of a Runt domain transcription factor AML1/RUNX1 in leukemogenesis and its clinical implications Crit Rev Oncol Hematol 2003; 45: 129-50.]. Disruption in each subunit will result in total loss of function of the CBF. Since both subunits are equally important for the function of the CBF, knock-in of the AML1-fusion gene exerts similar phenotype as a AML1 knockout [4Kurokawa M, Hirai H. Role of AML1/Runx1 in the pathogenesis of hematological malignancies Cancer Sci 2003; 94: 841-6., 28Krug U, Ganser A, Koeffler HP. Tumor suppressor genes in normal and malignant hematopoiesis Oncogene 2002; 21: 3475-95.]. This notion is supported by the fact that disruption of the CBFβ results in similar phenotype as the disruption of the AML1 [4Kurokawa M, Hirai H. Role of AML1/Runx1 in the pathogenesis of hematological malignancies Cancer Sci 2003; 94: 841-6., 30Adya N, Stacy T, Speck NA, et al. The leukemic protein core binding factor b (CBFb)-smooth-muscle myosin heavy chain sequesters CBF a 2 into cytoskeletal filaments and aggregates Mol Cell Biol 1998; 18: 7432-43., 34Kundu M, Chen A, Anderson S, et al. Role of CBFb in hematopoiesis and perturbations resulting from expression of the leukemogenic fusion gene CBFb -MYH11 Blood 2002; 100: 2449-56., 35Castilla LH, Wijmenga C, Wang Q, et al. Failure of embryonic hematopoiesis and lethal hemorrhages in mouse embryos heterozygous for a knocked-in leukemia gene CBFb-MYH11 Cell 1996; 87: 687-96.].

The CBF plays critical roles in lineage commitment of myeloid progenitors and terminal differentiation of hematopoietic cells [31Downing JR. The AML1-ETO chimaeric transcription factor in acute myeloid leukaemia: biology and clinical significance Br J Haematol 1999; 106: 296-308., 36Hart SM, Foroni L. Core binding factor genes and human leukemia Haematologica 2002; 87: 1307-23.]. Many myeloid-specific regulatory genes have cis-acting binding sites for AML1, and activation of these genes are believed to be critical for the normal granulocyte development [3Skalnik DG. Transcriptional mechanisms regulating myeloid-specific genes Gene 2002; 284: 1-21.]. When the function of the CBF is affected by leukemogenesis, the development of the granulocytes is also affected [37Scandura JM, Boccuni P, Cammenga J, et al. Transcription factor fusions in acute leukemia variations on a theme Oncogene 2002; 21: 3422-44.]. Although the CBFβ is ubiquitously expressed, its function is not well-studied [38Wang Q, Stacy T, Miller JD, et al. The CBFb subunit is essential for CBF a 2 (AML1) function in vivo Cell 1996; 87: 697-708.]. However, knockout of either AML1 or CBFβ in mice results in embryonic lethality [18Okuda T, vanDeursen J, Hiebert SW. AML1 the target of multiple chromosomal translocations in human leukemia is essential for normal fetal liver hematopoiesis Cell 1996; 84: 321-0., 22Li X, Vradii D, Gutierrez S, et al. Subnuclear targeting of Runx1 is required for synergistic activation of the myeloid specific M-CSF receptor promoter by PU J Cell Biochem 2005; 96: 795-809., 39Gilliland DG, Jordan CT, Felix CA. The molecular basis of leukemia Hematology (Am Soc Hematol Educ Prog) 2004; 00: 80-97.-42Levanon D, Groner Y. Structure and regulated expression of mammalian RUNX genes Oncogene 2004; 23: 4211-9.]. It is not clear whether AML1 or CBFβ contributes to fetal hematopoiesis through additional pathways. Identification of the upstream actors or downstream targets of the AML1 might be helpful in designing disease-specific therapeutic methodologies.

THE AML1 FUSIONS IN LEUKEMIA

The most commonly t(8;21), t(12;21), and t(3;21) for AML1 generate fusions that are frequently observed in M1 and M2 subtypes of myeloid leukemia [26Kundu M, Liu PP. Function of the inv(16) fusion gene CBFb-MYH11 Curr Opin Hematol 2001; 8: 201-5., 30Adya N, Stacy T, Speck NA, et al. The leukemic protein core binding factor b (CBFb)-smooth-muscle myosin heavy chain sequesters CBF a 2 into cytoskeletal filaments and aggregates Mol Cell Biol 1998; 18: 7432-43.]. The chromosomal translocation t(8;21) represents significant portion of the M2 subtype of AML [19Melnick A, Carlile GW, McConnell MJ, et al. AML-1/ETO fusion protein is a dominant negative inhibitor of transcriptional repression by the promyelocytic leukemia zinc finger protein Blood 2000; 96: 3939-47., 43Mulloy JC, Cammenga J, MacKenzie KL, et al. The AML1-ETO fusion protein promotes the expansion of human hematopoietic stem cells Blood 2002; 99: 15-23.-45Miyoshi H, Shimizu K, Kozu T, et al. Ohki M t (821) breakpoints on chromosome 21 in acute myeloid leukemia are clustered within a limited region of a single gene AML1 Proc Natl Acad Sci USA 1991; 88: 10431-4.]. This translocation fuses AML1 (RUNX1) to ETO creating a novel hybrid AML1/ETO gene [24Ma SK, Wan TS, Chan LC. Cytogenetics and molecular genetics of childhood leukemia Hematol Oncol 1999; 17: 91-105., 46Yuan Y, Zhou L, Miyamoto T, et al. AML1-ETO expression is directly involved in the development of acute myeloid leukemia in the presence of additional mutations Proc Natl Acad Sci USA 2001; 98: 10398-403.-53Vangala RK, Heiss-Neumann MS, Rangatia JS, et al. The myeloid master regulator transcription factor PU is inactivated by AML1-ETO i t(8; 1) myeloid leukemia. Blood 2003, 101: 270-7.]. The AML1-ETO interacts with other transcriptional factors act as repressors such as N-CoR, mSin3A and HDACs through its ETO part [9Barseguian K, Lutterbach B, Hiebert SW, et al. Multiple subnuclear targeting signals of the leukemia-related AML1/ETO and ETO repressor proteins Proc Natl Acad Sci USA 2002; 99: 15434-9., 33Asou N. The role of a Runt domain transcription factor AML1/RUNX1 in leukemogenesis and its clinical implications Crit Rev Oncol Hematol 2003; 45: 129-50., 37Scandura JM, Boccuni P, Cammenga J, et al. Transcription factor fusions in acute leukemia variations on a theme Oncogene 2002; 21: 3422-44.]. Thus, the fusion protein exhibits dominant negative effect over the wild type AML1 inhibiting transcription of the normally AML1-regulated genes that are essential for hematopoiesis [43Mulloy JC, Cammenga J, MacKenzie KL, et al. The AML1-ETO fusion protein promotes the expansion of human hematopoietic stem cells Blood 2002; 99: 15-23., 51Lutterbach B, Westendorf JJ, Linggi B, et al. ETO a target of t(8,21) in acute leukemia interacts with the N-CoR and mSin3 corepressors Mol Cell Biol 1998; 18: 7176-84., 54Hiebert SW, Lutterbach B, Amann J. Role of co-repressors in transcriptional repression mediated by the t(8,21) t(16,21) t(12,21) and inv(16) fusion proteins Curr Opin Hematol 2001; 8: 197-200.-56Follows GA, Tagoh H, Lefevre P, et al. Epigenetic consequences of AML1-ETO action at the human c-FMS locus EMBO J 2003; 22: 2798-809.]. Biological features of the fusion AML1-ETO is the disruption of hematopoiesis including the hypergranulation and strong myeloperoxidase-positivity of hematopoietic cells [31Downing JR. The AML1-ETO chimaeric transcription factor in acute myeloid leukaemia: biology and clinical significance Br J Haematol 1999; 106: 296-308., 57Mandelli F, Petti MC, LoCoco F. Therapy of acute myeloid leukemia towards a patient-oriented risk-adapted approach Haematologica 1998; 83: 1015-23., 58Nishida S, Hosen N, Shirakata T, et al. AML1-ETO rapidly induces acute myeloblastic leukemia in cooperation with the Wilms tumor gene WT1 Blood 2006; 107: 3303-12.].

TREATMENT RESPONSE IN PATIENTS WITH AML1-ETO

Choice of appropriate regimens for treatment of leukemias is mainly based on accurate diagnosis. The major treatment choice is the classical chemotherapy [10Bruserud O, Gjertsen BT, Huang T. Induction of differentiation and apoptosis- a possible strategy in the treatment of adult acute myelogenous leukemia Oncologist 2000; 5: 454-62.]. The M2 AML responds well to high dose cytarabine exhibiting high remission rate and long disease-free survival [57Mandelli F, Petti MC, LoCoco F. Therapy of acute myeloid leukemia towards a patient-oriented risk-adapted approach Haematologica 1998; 83: 1015-23.]. Particularly, the AML1/ETO is serving as a paradigm for the M2 subtype of AML due partly to its high percentage of incidence that constitutes about 40% the M2 subtype [43Mulloy JC, Cammenga J, MacKenzie KL, et al. The AML1-ETO fusion protein promotes the expansion of human hematopoietic stem cells Blood 2002; 99: 15-23., 58Nishida S, Hosen N, Shirakata T, et al. AML1-ETO rapidly induces acute myeloblastic leukemia in cooperation with the Wilms tumor gene WT1 Blood 2006; 107: 3303-12.]. Patients who harbor AML1/ETO fusion have favorable prognosis. Patients presenting AML1/ETO normally do not directly require bone marrow transplantation, and thus the transplantation related complications may be avoided in these patients [2Speck NA, Gilliland DG. Core-binding factors in haematopoiesis and leukaemia Nat Rev Cancer 2002; 2: 502-13.]. However, high dose cytarabine is associated with multiple side effects such as cardiovascular and central nervous system damages.

Leukemia Related to the Inv(16)

Inv(16) for CBFβ is a result of a pericentric inversion of chromosome 16 [4Kurokawa M, Hirai H. Role of AML1/Runx1 in the pathogenesis of hematological malignancies Cancer Sci 2003; 94: 841-6., 24Ma SK, Wan TS, Chan LC. Cytogenetics and molecular genetics of childhood leukemia Hematol Oncol 1999; 17: 91-105.-30Adya N, Stacy T, Speck NA, et al. The leukemic protein core binding factor b (CBFb)-smooth-muscle myosin heavy chain sequesters CBF a 2 into cytoskeletal filaments and aggregates Mol Cell Biol 1998; 18: 7432-43., 59Poirel H, Radford-Weiss I, Rack K, et al. Detection of the chromosome 16 CBF b-MYH11 fusion transcript in myelomono-cytic leukemias Blood 1995; 85: 1313-22.-61Liu P, Tarlé SA, Hajra A, et al. Fusion between transcription factor CBFb/PEBP2b and a myosin heavy chain in acute myeloid leukemia Science 1993; 261: 1041-4.]. This inversion results in fusion of the CBFβ in frame to a myosin heavy chain gene (MYH11), which is located on the short arm (16p13) of the chromosome [4Kurokawa M, Hirai H. Role of AML1/Runx1 in the pathogenesis of hematological malignancies Cancer Sci 2003; 94: 841-6., 30Adya N, Stacy T, Speck NA, et al. The leukemic protein core binding factor b (CBFb)-smooth-muscle myosin heavy chain sequesters CBF a 2 into cytoskeletal filaments and aggregates Mol Cell Biol 1998; 18: 7432-43., 59Poirel H, Radford-Weiss I, Rack K, et al. Detection of the chromosome 16 CBF b-MYH11 fusion transcript in myelomono-cytic leukemias Blood 1995; 85: 1313-22.]. This chromosomal abnormality creates a novel hybrid gene (CBFβ/MYH11), which is expressed to produce a CBFβ/SMMHC chimeric protein [4Kurokawa M, Hirai H. Role of AML1/Runx1 in the pathogenesis of hematological malignancies Cancer Sci 2003; 94: 841-6., 24Ma SK, Wan TS, Chan LC. Cytogenetics and molecular genetics of childhood leukemia Hematol Oncol 1999; 17: 91-105., 62Huang G, Shigesada K, Wee HJ, et al. Molecular basis for a dominant inactivation of RUNX1/AML1 by the leukemogenic inversion 16 chimera Blood 2004; 103: 3200-7., 63Tanaka Y, Fujii M, Hayashi K, et al. The chimeric protein PEBP2 b/CBF b-SMMHC disorganizes cytoplasmic stress fibers and inhibits transcriptional activation Oncogene 1998; 17: 699-708.]. The chimeric protein is composed of the first 165 amino acids of CBFβ and a half part of SMMHC including its coiled-coil domain [26Kundu M, Liu PP. Function of the inv(16) fusion gene CBFb-MYH11 Curr Opin Hematol 2001; 8: 201-5., 32Lukasik SM, Zhang L, Corpora T, et al. Altered affinity of CBF β-SMMHC for Runx1 explains its role in leukemogenesis Nat Struct Biol 2002; 9: 674-9., 62Huang G, Shigesada K, Wee HJ, et al. Molecular basis for a dominant inactivation of RUNX1/AML1 by the leukemogenic inversion 16 chimera Blood 2004; 103: 3200-7., 64Durst KL, Lutterbach B, Kummalue T, et al. The inv(16) fusion protein associates with corepressors via a smooth muscle myosin heavy-chain domain Mol Cell Biol 2003; 23: 607-19.]. The chimeric protein is still able to heterodimerize with AML1 [65Shurtleff SA, Meyers S, Hiebert SW, et al. Heterogeneity in CBF b/MYH11 fusion messages encoded by the inv(16)(p13q22) and the t(16,16)(p13,q22) in acute myelogenous leukemia Blood 1995; 85: 3695-703., 66Cao W, Adya N, Britos-Bray M, et al. The core binding factor (CBF) a interaction domain and the smooth muscle myosin heavy chain (SMMHC) segment of CBFb-SMMHC are both required to slow cell proliferation J Biol Chem 1998; 273: 31534-40.]. In fact, it has been reported that CBFβ/SMMHC binds to AML1 more avidly and with altered stochiometry [32Lukasik SM, Zhang L, Corpora T, et al. Altered affinity of CBF β-SMMHC for Runx1 explains its role in leukemogenesis Nat Struct Biol 2002; 9: 674-9.]. This translocation is exclusively associated with the M4eo subtype of AML [24Ma SK, Wan TS, Chan LC. Cytogenetics and molecular genetics of childhood leukemia Hematol Oncol 1999; 17: 91-105., 50LoCoco F, Pisegna S, Diverio D. The AML1 gene a transcription factor involved in the pathogenesis of myeloid and lymphoid leukemias Haematologica 1997; 82: 364-70., 59Poirel H, Radford-Weiss I, Rack K, et al. Detection of the chromosome 16 CBF b-MYH11 fusion transcript in myelomono-cytic leukemias Blood 1995; 85: 1313-22., 62Huang G, Shigesada K, Wee HJ, et al. Molecular basis for a dominant inactivation of RUNX1/AML1 by the leukemogenic inversion 16 chimera Blood 2004; 103: 3200-7., 67Shigesada K, vandeSluis B, Liu PP. Mechanism of leukemogenesis by the inv(16) chimeric gene CBFb/PEBP2b-MHY11 Oncogene 2004; 23: 4297-307.-70Schnittger S, Bacher U, Haferlach C. Rare CBFB-MYH11 fusion transcripts in AML with inv(16)/t(16,16) are associated with therapy-related AML M4eo atypical cytomorphology atypical immunophenotype, atypical additional chromosomal rearrange-ments and low white blood cell count a study on 162 patients Leukemia 2007; 21: 725-31.]. The M4eo is associated with abnormal eosinophils [12Burmeister T, Thiel E. Molecular genetics in acute and chronic leukemias J Cancer Res Clin Oncol 2001; 127: 80-90., 25Reilly JT. Pathogenesis of acute myeloid leukaemia and inv(16)(p13,q22) a paradigm for understanding leukaemogenesis Br J Haematol 2005; 128: 18-34., 26Kundu M, Liu PP. Function of the inv(16) fusion gene CBFb-MYH11 Curr Opin Hematol 2001; 8: 201-5., 30Adya N, Stacy T, Speck NA, et al. The leukemic protein core binding factor b (CBFb)-smooth-muscle myosin heavy chain sequesters CBF a 2 into cytoskeletal filaments and aggregates Mol Cell Biol 1998; 18: 7432-43., 59Poirel H, Radford-Weiss I, Rack K, et al. Detection of the chromosome 16 CBF b-MYH11 fusion transcript in myelomono-cytic leukemias Blood 1995; 85: 1313-22., 67Shigesada K, vandeSluis B, Liu PP. Mechanism of leukemogenesis by the inv(16) chimeric gene CBFb/PEBP2b-MHY11 Oncogene 2004; 23: 4297-307., 70Schnittger S, Bacher U, Haferlach C. Rare CBFB-MYH11 fusion transcripts in AML with inv(16)/t(16,16) are associated with therapy-related AML M4eo atypical cytomorphology atypical immunophenotype, atypical additional chromosomal rearrange-ments and low white blood cell count a study on 162 patients Leukemia 2007; 21: 725-31.]. The M4eo exhibits similar response to chemotherapy as that of the M2 subtype [40Yokomizo T, Ogawa M, Osato M, et al. Requirement of Runx1/AML1/PEBP2aB for the generation of haematopoietic cells from endothelial cells Genes Cells 2001; 6: 13-23.]. Similar to the AML1-ETO fusion, the CBFβ/SMMHC protein exerts dominant negative effect on the wild type AML1 [4Kurokawa M, Hirai H. Role of AML1/Runx1 in the pathogenesis of hematological malignancies Cancer Sci 2003; 94: 841-6., 27Licht JD, Sternberg DW. The molecular pathology of acute myeloid leukemia Hematology (Am Soc Hematol Educ Prog) 2005; 00: 137-42., 30Adya N, Stacy T, Speck NA, et al. The leukemic protein core binding factor b (CBFb)-smooth-muscle myosin heavy chain sequesters CBF a 2 into cytoskeletal filaments and aggregates Mol Cell Biol 1998; 18: 7432-43., 32Lukasik SM, Zhang L, Corpora T, et al. Altered affinity of CBF β-SMMHC for Runx1 explains its role in leukemogenesis Nat Struct Biol 2002; 9: 674-9., 35Castilla LH, Wijmenga C, Wang Q, et al. Failure of embryonic hematopoiesis and lethal hemorrhages in mouse embryos heterozygous for a knocked-in leukemia gene CBFb-MYH11 Cell 1996; 87: 687-96., 64Durst KL, Lutterbach B, Kummalue T, et al. The inv(16) fusion protein associates with corepressors via a smooth muscle myosin heavy-chain domain Mol Cell Biol 2003; 23: 607-19., 71Lutterbach B, Hou Y, Durst KL. The inv(16) encodes an acute myeloid leukemia 1 transcriptional corepressor Proc Natl Acad Sci USA 1999; 96: 12822-7., 72Castilla LH, Garrett L, Adya N. The fusion gene CBFb-MYH11 blocks myeloid differentiation and predisposes mice to acute myelomonocytic leukaemia Nat Genet 1999; 23: 144-6.]. The CBFβ/SMMHC can sequester the AML1 into nonfunctional complex thus acting as an inhibitor of the CBF [73Britos-Bray M, Ramirez M, Cao W, et al. CBFb-SMMHC expressed in M4eo acute myeloid leukemia reduces p53 induction and slows apoptosis in hematopoietic cells exposed to DNA-damaging agents Blood 1998; 92: 4344-52., 74Kummalue T, Lou J, Friedman AD. Multimerization via its myosin domain facilitates nuclear localization and inhibition of core binding factor (CBF) activities by the CBFb-smooth muscle myosin heavy chain myeloid leukemia oncoprotein Mol Cell Biol 2002; 22: 8278-91.]. Furthermore, the dominant inhibitory function of the CBFβ/SMMHC is partly attributed to sequesteration of the AML1 in the cytoplasm [26Kundu M, Liu PP. Function of the inv(16) fusion gene CBFb-MYH11 Curr Opin Hematol 2001; 8: 201-5., 28Krug U, Ganser A, Koeffler HP. Tumor suppressor genes in normal and malignant hematopoiesis Oncogene 2002; 21: 3475-95., 36Hart SM, Foroni L. Core binding factor genes and human leukemia Haematologica 2002; 87: 1307-23., 75Kanno Y, Kanno T, Sakakura C, et al. Cytoplasmic sequestration of the polyomavirus enhancer binding protein 2 (PEBP2)/core binding factor a (CBF a) subunit by the leukemia-related PEBP2/CBFb-SMMHC fusion protein inhibits PEBP2/CBF-mediated transactivation Mol Cell Biol 1998; 18: 4252-61.]. Mice chimeras that express CBFβ/SMMHC exhibit a phenotype similar to AML1 or CBFβ null mice [28Krug U, Ganser A, Koeffler HP. Tumor suppressor genes in normal and malignant hematopoiesis Oncogene 2002; 21: 3475-95., 63Tanaka Y, Fujii M, Hayashi K, et al. The chimeric protein PEBP2 b/CBF b-SMMHC disorganizes cytoplasmic stress fibers and inhibits transcriptional activation Oncogene 1998; 17: 699-708., 72Castilla LH, Garrett L, Adya N. The fusion gene CBFb-MYH11 blocks myeloid differentiation and predisposes mice to acute myelomonocytic leukaemia Nat Genet 1999; 23: 144-6., 73Britos-Bray M, Ramirez M, Cao W, et al. CBFb-SMMHC expressed in M4eo acute myeloid leukemia reduces p53 induction and slows apoptosis in hematopoietic cells exposed to DNA-damaging agents Blood 1998; 92: 4344-52.], and these observations emphasize that the inv(16) most likely exploit similar biochemical mechanisms that are exploited by the other CBF leukemias to establish its effects.

Leukemia Related to the t(3; 21)

This chromosomal translocation is relatively rare and it is tightly associated with chemotherapy-related myelodys-plastic syndrome (MDS) and chronic myelogenous leukemia (CML) [4Kurokawa M, Hirai H. Role of AML1/Runx1 in the pathogenesis of hematological malignancies Cancer Sci 2003; 94: 841-6., 21Perry C, Eldor A, Soreq H. Runx1/AML1 in leukemia disrupted association with diverse protein partners Leuk Res 2002; 26: 221-8., 76Zent CS, Mathieu C, Claxton DF, et al. The chimeric genes AML1/MDS1 and AML1/EAP inhibit AML1B activation at the CSF1R promoter, but only AML1/MDS1 has tumor-promoter properties Proc Natl Acad Sci USA 1996; 93: 1044-8.]. This translocation fuses AML1 to EPA, MDS1 or EVI1, depending on the location of the breakpoint within chromosome 3, because all the three genes are located within the same region of the long arm of the chromosome [21Perry C, Eldor A, Soreq H. Runx1/AML1 in leukemia disrupted association with diverse protein partners Leuk Res 2002; 26: 221-8., 50LoCoco F, Pisegna S, Diverio D. The AML1 gene a transcription factor involved in the pathogenesis of myeloid and lymphoid leukemias Haematologica 1997; 82: 364-70., 77Yin CC, Cortes J, Barkoh B, et al. t(3,21)(q26,q22) in myeloid leukemia an aggressive syndrome of blast transformation associated with hydroxyurea or antimetabolite therapy Cancer 2006; 106: 1730-8.]. In any case, transcription of the fusion gene is driven by AML1 promoter [78Kurokawa M, Mitani K, Imai Y, et al. The t(3,21) fusion product AML1/Evi-1 interacts with Smad3 and blocks transforming growth factor-b-mediated growth inhibition of myeloid cells Blood 1998; 92: 4003-12.]. The t(3; 21) may be induced by the chemotherapeutic agents including topoisomerase II inhibitors in patients [21Perry C, Eldor A, Soreq H. Runx1/AML1 in leukemia disrupted association with diverse protein partners Leuk Res 2002; 26: 221-8.]. EAP is a highly expressed small nuclear proteins related to Epstein-Barr virus small RNA [21Perry C, Eldor A, Soreq H. Runx1/AML1 in leukemia disrupted association with diverse protein partners Leuk Res 2002; 26: 221-8.]. MDS1 encodes for small RNA of unknown function, while EVI1 gene encodes a zinc finger transcription factor that seems to be involved in transactivation of some genes [21Perry C, Eldor A, Soreq H. Runx1/AML1 in leukemia disrupted association with diverse protein partners Leuk Res 2002; 26: 221-8., 78Kurokawa M, Mitani K, Imai Y, et al. The t(3,21) fusion product AML1/Evi-1 interacts with Smad3 and blocks transforming growth factor-b-mediated growth inhibition of myeloid cells Blood 1998; 92: 4003-12.-80Kurokawa M, Mitani K, Irie K, et al. The oncoprotein Evi-1 represses TGF-b signalling by inhibiting Smad3 Nature 1998; 394: 92-6.] such as c-Fos [21Perry C, Eldor A, Soreq H. Runx1/AML1 in leukemia disrupted association with diverse protein partners Leuk Res 2002; 26: 221-8.]. In summary, all the AML1-fusion products disrupt the normal function of the AML1, resulting in similar overall disease characteristics of the AML [4Kurokawa M, Hirai H. Role of AML1/Runx1 in the pathogenesis of hematological malignancies Cancer Sci 2003; 94: 841-6., 27Licht JD, Sternberg DW. The molecular pathology of acute myeloid leukemia Hematology (Am Soc Hematol Educ Prog) 2005; 00: 137-42.].

TREATMENT RESPONSE IN PATIENTS WITH CBF FUSIONS

The CBF leukemias are responsive to the standard chemotherapy regimens such as the combination of anthracyclines and cytarabine (Ara-C) [57Mandelli F, Petti MC, LoCoco F. Therapy of acute myeloid leukemia towards a patient-oriented risk-adapted approach Haematologica 1998; 83: 1015-23.]. The intention of induction therapy is to achieve a clinical remission [10Bruserud O, Gjertsen BT, Huang T. Induction of differentiation and apoptosis- a possible strategy in the treatment of adult acute myelogenous leukemia Oncologist 2000; 5: 454-62.]. Once clinical remission is achieved, it is followed by postremission therapy which can be categorized as consolidation therapy or maintenance therapy. The purpose of consolidation therapy is to eradicate residual leukemic cells [10Bruserud O, Gjertsen BT, Huang T. Induction of differentiation and apoptosis- a possible strategy in the treatment of adult acute myelogenous leukemia Oncologist 2000; 5: 454-62.], while maintenance therapy is to preventing relapse. However most of the chemotherapeutic agents are not specific to the leukemic cells. They also attack the normal cells that are actively dividing. Such cells include the skin cells, immune cells, hair follicles, and cells of gastrointestinal lining. Therefore, the reversible side effects include skin rush, hair loss, nausea, vomiting, diarrhea, and poor appetite are frequently associated with the treatment. The irreversible side effects may further include permanent organ damage and introduction of secondary malignancies. Thus, although chemotherapy is effective for treatment of leukemia, it is an urgent need for develop novel treatment agents that can minimize the side-effects.

THE RETINOIC ACID RECEPTOR a (RAR a)

Within the steroid/thyroid nuclear receptors, the subfamily of the retinoic acid receptors is composed of RARs and RXRs, each consisting of different isotypes (α, β, and γ) and each isotype is encoded by different genes [81Douer D. Transcription therapy for acute promyelocytic leukaemia Expert Opin Investig Drugs 2000; 9: 329-46., 82Chambon PA. Decade of molecular biology of retinoic acid receptors FASEB J 1996; 10: 940-54.]. All of the RAR family members (RARα, β, and γ) are activated by retinoic acids (RAs) [82Chambon PA. Decade of molecular biology of retinoic acid receptors FASEB J 1996; 10: 940-54.]. The RARα is a ligand-activated nuclear transcription factor [68Berman JN, Look AT. Targeting transcription factors in acute leukemia in children Curr Drug Targets 2007; 8: 727-37., 81Douer D. Transcription therapy for acute promyelocytic leukaemia Expert Opin Investig Drugs 2000; 9: 329-46., 83Mistry AR, Pedersen EW, Solomon E, et al. The molecular pathogenesis of acute promyelocytic leukaemia implications for the clinical management of the disease Blood Rev 2003; 17: 71-97., 84Melnick A, Licht JD. Deconstructing a disease RAR a its fusion partners and their roles in the pathogenesis of acute promyelocytic leukemia Blood 1999; 93: 3167-215.]. Retinoid-induced RARα regulate various cellular processes form embryonic development to maintenance of homeostasis and induction of cell death in adults [85Fontana JA, Rishi AK. Classical and novel retinoids their targets in cancer therapy Leukemia 2002; 16: 463-72., 82Chambon PA. Decade of molecular biology of retinoic acid receptors FASEB J 1996; 10: 940-54.]. RARα functions as a heterodimer and its heterodimeric partner is the RXRα [83Mistry AR, Pedersen EW, Solomon E, et al. The molecular pathogenesis of acute promyelocytic leukaemia implications for the clinical management of the disease Blood Rev 2003; 17: 71-97., 86Drumea K, Yang ZF, Rosmarin A. Retinoic acid signaling in myelopoiesis Curr Opin Hematol 2008; 15: 37-41.]. In the absence of the ligands, the RARα/RXRα heterodimers are believed to function as transcriptional inhibitors. The binding of the ligands coverts these transcriptional inhibitors into transcriptional activators, possibly by inducing conformational changes. The activated RARs in general bind to the response elements within the promoter regions of the RARα-regulated genes and induce gene expression, in general [83Mistry AR, Pedersen EW, Solomon E, et al. The molecular pathogenesis of acute promyelocytic leukaemia implications for the clinical management of the disease Blood Rev 2003; 17: 71-97., 87Lefebvre B, Brand C, Lefebvre P, et al. Chromosomal integration of retinoic acid response elements prevents cooperative transcriptional activation by retinoic acid receptor and retinoid X receptor Mol Cell Biol 2002; 22: 1446-59.]. Since the RARs are pleiotropic, treatment of multipotent cells such as FDCP mixA4 with erythropoietin results in inhibition of RARα and commitment of the cells into erythroid lineage, while treatment with G-CSF results in upregulation of expression of RARα resulting in commitment of the cells into myeloid lineage [84Melnick A, Licht JD. Deconstructing a disease RAR a its fusion partners and their roles in the pathogenesis of acute promyelocytic leukemia Blood 1999; 93: 3167-215., 88Collins SJ. The role of retinoids and retinoic acid receptors in normal hematopoiesis Leukemia 2002; 16: 1896-905.]. Lines of evidence strengthen the notion that the AR/RARα signaling is necessary for neutrophil maturation. Transgenic mice harboring a mutation within ligand-binding domain of RARα exhibit increased immature neutrophil cell count suggesting the importance of RARα in neutrophil maturation [83Mistry AR, Pedersen EW, Solomon E, et al. The molecular pathogenesis of acute promyelocytic leukaemia implications for the clinical management of the disease Blood Rev 2003; 17: 71-97.]. The RARα pathway also plays very important roles driving the pluripotent hematopoietic cells along the granulocytic lineage [88Collins SJ. The role of retinoids and retinoic acid receptors in normal hematopoiesis Leukemia 2002; 16: 1896-905.-90Tocci A, Parolini I, Gabbianelli M. Dual action of retinoic acid on human embryonic/fetal hematopoiesis blockade of primitive progenitor proliferation and shift from multipotent/eryth-roid/monocytic to granulocytic differentiation program Blood 1996; 88: 2878-88.].

RARα ASSOCIATED FUSIONS IN SUBTYPES OF ACUTE MYELOID LEUKEMIA

The APL is a subtype of AML with a differentiation blockage at a promyelocytic stage of myeloid cell maturation [81Douer D. Transcription therapy for acute promyelocytic leukaemia Expert Opin Investig Drugs 2000; 9: 329-46., 91Duprez E, Wagner K, Koch H, et al. C/EBPb a major PML-RARa-responsive gene in retinoic acid-induced differentiation of APL cells EMBO J 2003; 22: 5806-16., 92Merghoub T, Gurrieri C, Piazza F. Modeling acute promye-locytic leukemia in the mouse new insights in the pathogenesis of human leukemias Blood Cells Mol Dis 2001; 27: 231-48.]. Thus, the APL is characterized by expansion or proliferation of the myeloid lineage blocked at a promyelocyte stage of differentiation [10Bruserud O, Gjertsen BT, Huang T. Induction of differentiation and apoptosis- a possible strategy in the treatment of adult acute myelogenous leukemia Oncologist 2000; 5: 454-62., 92Merghoub T, Gurrieri C, Piazza F. Modeling acute promye-locytic leukemia in the mouse new insights in the pathogenesis of human leukemias Blood Cells Mol Dis 2001; 27: 231-48.-94Meani N, Minardi S, Licciulli S, et al. Molecular signature of retinoic acid treatment in acute promyelocytic leukemia Oncogene 2005; 24: 3358-68.]. This group of disease is generally categorized as a FAB M3 subtype of the AML, while the t(15;17) is the most representative of the group. The unique cytogenetic abnormalities that are tightly associated with APL are the chromosomal translocations that target RARα [81Douer D. Transcription therapy for acute promyelocytic leukaemia Expert Opin Investig Drugs 2000; 9: 329-46., 95Hummel JL, Zhang T, Wells RA, et al. The retinoic acid receptor a (RAR a) chimeric proteins PML- PLZF- NPM- and NuMA-RAR a have distinct intracellular localization patterns Cell Growth Differ 2002; 13: 173-83.]. The genetic abnormalities underlying the initiation or the progression or the manifestation of APL include the chromosomal translocations t(15;17)(q22;q21), t(11;17)(q23;q21), t(11;17)(q13;q21), t(5;17)(q35;q21) and der(17) [83Mistry AR, Pedersen EW, Solomon E, et al. The molecular pathogenesis of acute promyelocytic leukaemia implications for the clinical management of the disease Blood Rev 2003; 17: 71-97.]. These reciprocal chromosomal translocations fuse RARα to different partners such as PML, PLZF, NuMA, NPM, and STAT5b respectively [15Kalantry S, Delva L, Gaboli M, et al. Gene rearrangements in the molecular pathogenesis of acute promyelocytic leukemia J Cell Physiol 1997; 173: 288-96., 81Douer D. Transcription therapy for acute promyelocytic leukaemia Expert Opin Investig Drugs 2000; 9: 329-46., 96Rego EM, Ruggero D, Tribioli C, et al. Leukemia with distinct phenotypes in transgenic mice expressing PML/RAR a PLZF/RAR a or NPM/RAR a Oncogene 2006; 25: 1974-9.-98Pandolfi PP. Oncogenes and tumor suppressors in the molecular pathogenesis of acute promyelocytic leukemia Hum Mol Genet 2001; 10: 769-5.].

The leukemia that is cytogenetically characterized as having the t(15;17) chromosomal translocation is categorized as the M3 subtype of AML, which is also known as APL [89Gratas C, Menot ML, Dresch C, et al. Retinoid acid supports granulocytic but not erythroid differentiation of myeloid progenitors in normal bone marrow cells Leukemia 1993; 7: 1156-62., 98Pandolfi PP. Oncogenes and tumor suppressors in the molecular pathogenesis of acute promyelocytic leukemia Hum Mol Genet 2001; 10: 769-5.-102Rego EM, He LZ, Warrell RPJr, et al. Retinoic acid (RA) and As2O3 treatment in transgenic models of acute promyelocytic leukemia (APL) unravel the distinct nature of the leukemogenic process induced by the PML-RAR a and PLZF-RAR a oncoproteins Proc Natl Acad Sci USA 2000; 97: 10173-8.]. The t(15;17)(q22;q21) is the most common form of the chromosomal translocations that target RARα, and seems to be responsible for transformed phenotype of APL [12Burmeister T, Thiel E. Molecular genetics in acute and chronic leukemias J Cancer Res Clin Oncol 2001; 127: 80-90., 15Kalantry S, Delva L, Gaboli M, et al. Gene rearrangements in the molecular pathogenesis of acute promyelocytic leukemia J Cell Physiol 1997; 173: 288-96., 68Berman JN, Look AT. Targeting transcription factors in acute leukemia in children Curr Drug Targets 2007; 8: 727-37., 81Douer D. Transcription therapy for acute promyelocytic leukaemia Expert Opin Investig Drugs 2000; 9: 329-46., 83Mistry AR, Pedersen EW, Solomon E, et al. The molecular pathogenesis of acute promyelocytic leukaemia implications for the clinical management of the disease Blood Rev 2003; 17: 71-97., 88Collins SJ. The role of retinoids and retinoic acid receptors in normal hematopoiesis Leukemia 2002; 16: 1896-905., 91Duprez E, Wagner K, Koch H, et al. C/EBPb a major PML-RARa-responsive gene in retinoic acid-induced differentiation of APL cells EMBO J 2003; 22: 5806-16.]. This chromosomal translocation represents over 95% clinically relevant APL cases [1Lutz PG, Moog-Lutz C, Cayre YE. Signaling revisited in acute promyelocytic leukemia Leukemia 2002; 16: 1933-9., 27Licht JD, Sternberg DW. The molecular pathology of acute myeloid leukemia Hematology (Am Soc Hematol Educ Prog) 2005; 00: 137-42., 83Mistry AR, Pedersen EW, Solomon E, et al. The molecular pathogenesis of acute promyelocytic leukaemia implications for the clinical management of the disease Blood Rev 2003; 17: 71-97.]. The PML/RARα may disrupt the normal function of RARα and PML [24Ma SK, Wan TS, Chan LC. Cytogenetics and molecular genetics of childhood leukemia Hematol Oncol 1999; 17: 91-105., 98Pandolfi PP. Oncogenes and tumor suppressors in the molecular pathogenesis of acute promyelocytic leukemia Hum Mol Genet 2001; 10: 769-5.]. APL that harbors PML/RARα fusion respond well to the current therapeutic regimens and exhibit favorable prognosis [101Koken MH, Reid A, Quignon F, et al. Leukemia-associated retinoic acid receptor a fusion partners PML and PLZF heterodimerize and colocalize to nuclear bodies Proc Natl Acad Sci USA 1997; 94: 10255-60., 102Rego EM, He LZ, Warrell RPJr, et al. Retinoic acid (RA) and As2O3 treatment in transgenic models of acute promyelocytic leukemia (APL) unravel the distinct nature of the leukemogenic process induced by the PML-RAR a and PLZF-RAR a oncoproteins Proc Natl Acad Sci USA 2000; 97: 10173-8.].

The t(11;17)(q23;q21) is also clinically relevant accounting for about 0.8% of APL cases [83Mistry AR, Pedersen EW, Solomon E, et al. The molecular pathogenesis of acute promyelocytic leukaemia implications for the clinical management of the disease Blood Rev 2003; 17: 71-97.]. This translocation fuses PLZF in frame to RARα creating a disease-specific hybrid gene (PLZF/RARα) [83Mistry AR, Pedersen EW, Solomon E, et al. The molecular pathogenesis of acute promyelocytic leukaemia implications for the clinical management of the disease Blood Rev 2003; 17: 71-97., 103Chen SJ, Zelent A, Tong JH, et al. Rearrangements of the retinoic acid receptor a and promyelocytic leukemia zinc finger genes resulting from t(11,17)(q23,q21) in a patient with acute promyelocytic leukemia J Clin Invest 1993; 91: 2260-7.]. PLZF is a zinc finger transcription factor which seems to be expressed during early stage of hematopoietic cell development [83Mistry AR, Pedersen EW, Solomon E, et al. The molecular pathogenesis of acute promyelocytic leukaemia implications for the clinical management of the disease Blood Rev 2003; 17: 71-97., 104Chen Z, Brand NJ, Chen A, et al. Fusion between a novel Kruppel-like zinc finger gene and the retinoic acid receptor- a locus due to a variant t(11,17) translocation associated with acute promyelocytic leukaemia EMBO J 1993; 12: 1161-7.]. PLZF may play important roles in maintenance or survival of early progenitor cells. PZLF is also known to regulate some powerful regulatory genes such as c-myc, cyclin A2. Therefore, PZLF may have direct or indirect tumor-suppressor activity that is disrupted by the chromosomal translocation. Unlike the PML/RARα containing cells, the PLZF/RARα containing cells do not respond to ATRA [81Douer D. Transcription therapy for acute promyelocytic leukaemia Expert Opin Investig Drugs 2000; 9: 329-46., 98Pandolfi PP. Oncogenes and tumor suppressors in the molecular pathogenesis of acute promyelocytic leukemia Hum Mol Genet 2001; 10: 769-5.].

The t(5;21)(q35;q21) only represents less than 0.5% of the clinically relevant APL cases [83Mistry AR, Pedersen EW, Solomon E, et al. The molecular pathogenesis of acute promyelocytic leukaemia implications for the clinical management of the disease Blood Rev 2003; 17: 71-97.]. This translocation fuses NPM in frame with RARα again creating a disease-specific hybrid gene [83Mistry AR, Pedersen EW, Solomon E, et al. The molecular pathogenesis of acute promyelocytic leukaemia implications for the clinical management of the disease Blood Rev 2003; 17: 71-97.]. The NPM/RARα fusion protein is believed to disrupt the normal function of RARα [83Mistry AR, Pedersen EW, Solomon E, et al. The molecular pathogenesis of acute promyelocytic leukaemia implications for the clinical management of the disease Blood Rev 2003; 17: 71-97.]. NPM is a nuclear phosphoprotein that is ubiquitously expressed [83Mistry AR, Pedersen EW, Solomon E, et al. The molecular pathogenesis of acute promyelocytic leukaemia implications for the clinical management of the disease Blood Rev 2003; 17: 71-97., 105Colombo E, Marine JC, Danovi D, et al. Nucleophosmin regulates the stability and transcriptional activity of p53 Nat Cell Biol 2002; 4: 529-33.]. Its main function is believed to be transportation of ribosomal materials between the nucleolus and the cytoplasm [83Mistry AR, Pedersen EW, Solomon E, et al. The molecular pathogenesis of acute promyelocytic leukaemia implications for the clinical management of the disease Blood Rev 2003; 17: 71-97.]. NPM is also a target of other chromosomal translocations [83Mistry AR, Pedersen EW, Solomon E, et al. The molecular pathogenesis of acute promyelocytic leukaemia implications for the clinical management of the disease Blood Rev 2003; 17: 71-97.], implying involvement of the protein in important regulatory processes. This protein is also implicated in regulation of p53, because it was found directly binding and stabilizing p53 in the events such as cellular stresses that induce expression of p53 [83Mistry AR, Pedersen EW, Solomon E, et al. The molecular pathogenesis of acute promyelocytic leukaemia implications for the clinical management of the disease Blood Rev 2003; 17: 71-97., 105Colombo E, Marine JC, Danovi D, et al. Nucleophosmin regulates the stability and transcriptional activity of p53 Nat Cell Biol 2002; 4: 529-33.]. The APL cells that harbor the t(5;17)(q35;q21) have favorable prognosis because they respond well to ATRA treatment [81Douer D. Transcription therapy for acute promyelocytic leukaemia Expert Opin Investig Drugs 2000; 9: 329-46., 83Mistry AR, Pedersen EW, Solomon E, et al. The molecular pathogenesis of acute promyelocytic leukaemia implications for the clinical management of the disease Blood Rev 2003; 17: 71-97.].

The t(11;17)(q13;q21) is a rare chromosomal translocation that fuses NuMA to RARα [83Mistry AR, Pedersen EW, Solomon E, et al. The molecular pathogenesis of acute promyelocytic leukaemia implications for the clinical management of the disease Blood Rev 2003; 17: 71-97.]. This translocation also exhibit favorable prognosis because it is sensitivity to ATRA [83Mistry AR, Pedersen EW, Solomon E, et al. The molecular pathogenesis of acute promyelocytic leukaemia implications for the clinical management of the disease Blood Rev 2003; 17: 71-97.]. NuMA seems to have important roles in mitosis, specifically in formation of spindle asters, and in re-formation of daughter nuclei [83Mistry AR, Pedersen EW, Solomon E, et al. The molecular pathogenesis of acute promyelocytic leukaemia implications for the clinical management of the disease Blood Rev 2003; 17: 71-97., 106Hsu HL, Yeh NH. Dynamic changes of NuMA during the cell cycle and possible appearance of a truncated form of NuMA during apoptosis J Cell Sci 1996; 109: 277-88.], and microtubule assembly [107Dionne MA, Howard L, Compton DA. NuMA is a component of an insoluble matrix at mitotic spindle poles Cell Motil Cytoskeleton 1999; 42: 189-203.]. Like the other RARα partners, RARα-NuMA disrupts the normal function of RARα and may lead to the leukemogenesis [81Douer D. Transcription therapy for acute promyelocytic leukaemia Expert Opin Investig Drugs 2000; 9: 329-46., 83Mistry AR, Pedersen EW, Solomon E, et al. The molecular pathogenesis of acute promyelocytic leukaemia implications for the clinical management of the disease Blood Rev 2003; 17: 71-97.].

In der (17) chromosomal abnormality, an interstitial deletion spanning a 3Mb DNA region on the long arm of chromosome 17 results in the fusion of STAT4b with RARα [83Mistry AR, Pedersen EW, Solomon E, et al. The molecular pathogenesis of acute promyelocytic leukaemia implications for the clinical management of the disease Blood Rev 2003; 17: 71-97.]. This event is very rare and its response to therapeutic regimens has not been determined. The STAT5b belongs to a family of transcription factors that are involved in multiple cellular processes and their aberrant expression is implicated in many cancer types including leukemia [83Mistry AR, Pedersen EW, Solomon E, et al. The molecular pathogenesis of acute promyelocytic leukaemia implications for the clinical management of the disease Blood Rev 2003; 17: 71-97.]. STAT5b is widely expressed including in hematopoietic progenitors [83Mistry AR, Pedersen EW, Solomon E, et al. The molecular pathogenesis of acute promyelocytic leukaemia implications for the clinical management of the disease Blood Rev 2003; 17: 71-97.]. Like the other RARα partners, this protein heterodimerizes with its coiled-coil motif. Disruption of the normal function of RARα as well as that of STAT5b could contribute to the leukemogenesis, although the function of STAT5b is not known.

TREATMENT RESPONSE IN PATIENTS WITH RARΑ FUSIONS

The most studied and better understood mechanism exploited by the fusion proteins is to recruit the transcriptional corepressors to the RARα regulated gene promoters, thus preventing RARα to activate its targeting genes that are important for hematopoiesis [33Asou N. The role of a Runt domain transcription factor AML1/RUNX1 in leukemogenesis and its clinical implications Crit Rev Oncol Hematol 2003; 45: 129-50., 108Atsumi A, Tomita A, Kiyoi H, et al. Histone deacetylase 3 (HDAC3) is recruited to target promoters by PML-RAR a as a component of the N-CoR co-repressor complex to repress transcription in vivo Biochem Biophys Res Commun 2006; 345: 1471-80.]. It has been established that RARα and AML1 interacts with corepressors including N-CoR, mSin3A and HDACs [4Kurokawa M, Hirai H. Role of AML1/Runx1 in the pathogenesis of hematological malignancies Cancer Sci 2003; 94: 841-6., 21Perry C, Eldor A, Soreq H. Runx1/AML1 in leukemia disrupted association with diverse protein partners Leuk Res 2002; 26: 221-8., 51Lutterbach B, Westendorf JJ, Linggi B, et al. ETO a target of t(8,21) in acute leukemia interacts with the N-CoR and mSin3 corepressors Mol Cell Biol 1998; 18: 7176-84., 109Lausen J, Cho S, Liu S, et al. The nuclear receptor co-repressor (N-CoR) utilizes repression domains I and III for interaction and co-repression with ETO J Biol Chem 2004; 279: 49281-8.-112Amann JM, Nip J, Strom DK, et al. ETO a target of t(8,21) in acute leukemia makes distinct contacts with multiple histone deacetylases and binds mSin3A through its oligomerization domain Mol Cell Biol 2001; 21: 6470-83.]. The classical treatment of APL is the intensive chemotherapy. Overall, APL exhibits favorable prognosis due to its sensitivity to treatment in general [113He LZ, Tolentino T, Grayson P, et al. Histone deacetylase inhibitors induce remission in transgenic models of therapy-resistant acute promyelocytic leukemia J Clin Invest 2001; 108: 1321-30.]. During the last 15 years, ATRA has become the mainstay of the treatment of APL [86Drumea K, Yang ZF, Rosmarin A. Retinoic acid signaling in myelopoiesis Curr Opin Hematol 2008; 15: 37-41., 96Rego EM, Ruggero D, Tribioli C, et al. Leukemia with distinct phenotypes in transgenic mice expressing PML/RAR a PLZF/RAR a or NPM/RAR a Oncogene 2006; 25: 1974-9., 114Guidez F, Ivins S, Zhu J, et al. Reduced retinoic acid-sensitivities of nuclear receptor corepressor binding to PML- and PLZF-RAR a underlie molecular pathogenesis and treatment of acute promyelocytic leukemia Blood 1998; 91: 2634-42.]. Although a physiological concentration of ATRA is not effective, a pharmacological concentration of ATRA causes terminal differentiation of leukemic cells, and results in long term survival in APL patients [86Drumea K, Yang ZF, Rosmarin A. Retinoic acid signaling in myelopoiesis Curr Opin Hematol 2008; 15: 37-41., 88Collins SJ. The role of retinoids and retinoic acid receptors in normal hematopoiesis Leukemia 2002; 16: 1896-905., 115Glasow A, Prodromou N, Xu K, et al. Retinoids and myelomonocytic growth factors cooperatively activate RARa and induce human myeloid leukemia cell differentiation via MAP kinase pathways Blood 2005; 105: 341-9., 116Pitha-Rowe I, Petty WJ, Kitareewan S, et al. Retinoid target genes in acute promyelocytic leukemia Leukemia 2003; 17: 1723-30.]. Furthermore, simultaneous administration of chemotherapy and ATRA has improved the remission rate and significant reduction of relapse risk [10Bruserud O, Gjertsen BT, Huang T. Induction of differentiation and apoptosis- a possible strategy in the treatment of adult acute myelogenous leukemia Oncologist 2000; 5: 454-62., 97Grimwade D, LoCoco F. Acute promyelocytic leukemia a model for the role of molecular diagnosis and residual disease monitoring in directing treatment approach in acute myeloid leukemia Leukemia 2002; 16: 1959-73.]. This combination therapy is more effective than either chemotherapy or ATRA alone and improved an overall survival rate [10Bruserud O, Gjertsen BT, Huang T. Induction of differentiation and apoptosis- a possible strategy in the treatment of adult acute myelogenous leukemia Oncologist 2000; 5: 454-62., 97Grimwade D, LoCoco F. Acute promyelocytic leukemia a model for the role of molecular diagnosis and residual disease monitoring in directing treatment approach in acute myeloid leukemia Leukemia 2002; 16: 1959-73.]. Although the mechanism of action of ATRA is not clear, it is believed that ATRA forces the APL cells into neutrophil-like differentiation [81Douer D. Transcription therapy for acute promyelocytic leukaemia Expert Opin Investig Drugs 2000; 9: 329-46., 84Melnick A, Licht JD. Deconstructing a disease RAR a its fusion partners and their roles in the pathogenesis of acute promyelocytic leukemia Blood 1999; 93: 3167-215., 85Fontana JA, Rishi AK. Classical and novel retinoids their targets in cancer therapy Leukemia 2002; 16: 463-72., 88Collins SJ. The role of retinoids and retinoic acid receptors in normal hematopoiesis Leukemia 2002; 16: 1896-905.], which ultimately leads to apoptosis [81Douer D. Transcription therapy for acute promyelocytic leukaemia Expert Opin Investig Drugs 2000; 9: 329-46.]. ATRA acts through the RARα signaling pathway [82Chambon PA. Decade of molecular biology of retinoic acid receptors FASEB J 1996; 10: 940-54., 84Melnick A, Licht JD. Deconstructing a disease RAR a its fusion partners and their roles in the pathogenesis of acute promyelocytic leukemia Blood 1999; 93: 3167-215.]. ATRA is also is believed to be involved in interferon signaling pathways because induction of interferon regulatory factor-1 (IRF-1) has been observed during ATRA treatment, and IRF-1 induces expression of interferons, which ultimately lead to apoptosis and cell death [84Melnick A, Licht JD. Deconstructing a disease RAR a its fusion partners and their roles in the pathogenesis of acute promyelocytic leukemia Blood 1999; 93: 3167-215.]. Most recently, use of an old medicine, As2O3, in APL has proven useful because it induces apoptosis in APL cells that are resistant to ATRA [81Douer D. Transcription therapy for acute promyelocytic leukaemia Expert Opin Investig Drugs 2000; 9: 329-46.]. Furthermore, As2O3 has proven itself to be effective to treat the APL patients at disease recurrence [97Grimwade D, LoCoco F. Acute promyelocytic leukemia a model for the role of molecular diagnosis and residual disease monitoring in directing treatment approach in acute myeloid leukemia Leukemia 2002; 16: 1959-73.].

Although positive results have been achieved in treating APL, significant problems remain to be solved. For instance, APL is linked to bleeding diathesis which occurs during early stage of the treatment. The bleeding seems to occur due to disseminated intravascular coagulation and excessive fibrinolysis [81Douer D. Transcription therapy for acute promyelocytic leukaemia Expert Opin Investig Drugs 2000; 9: 329-46.]. Severe coagulation that can lead to hemorrhagic complications has become clinical feature of the disease [97Grimwade D, LoCoco F. Acute promyelocytic leukemia a model for the role of molecular diagnosis and residual disease monitoring in directing treatment approach in acute myeloid leukemia Leukemia 2002; 16: 1959-73.]. The coagulopathy is usually triggered or more exacerbated by chemotherapy leading to high induction death rate at 10%, meanwhile increased awareness has resulted in better supportive care that resulted in decreased induction death [97Grimwade D, LoCoco F. Acute promyelocytic leukemia a model for the role of molecular diagnosis and residual disease monitoring in directing treatment approach in acute myeloid leukemia Leukemia 2002; 16: 1959-73.]. The side effects including fever, respiratory distress, pleural or pericardial effusion and interstitial lung infiltration usually occur during the first month of treatment and occasionally immediately after administration of the first dose of ATRA [81Douer D. Transcription therapy for acute promyelocytic leukaemia Expert Opin Investig Drugs 2000; 9: 329-46.]. These side effects are so serious that if left untreated, they can lead to hypoxia, respiratory failure and ultimate death [81Douer D. Transcription therapy for acute promyelocytic leukaemia Expert Opin Investig Drugs 2000; 9: 329-46.]. Other common and reversible side effects associated with ATRA treatment are headache, dry skin and mucosal membrane [81Douer D. Transcription therapy for acute promyelocytic leukaemia Expert Opin Investig Drugs 2000; 9: 329-46.]. Hence, better treatment methods and regimens that eliminate the unnecessary side effects that affect the quality of life of the patients are urgently needed.

THE COMMON CHARACTERISTICS OF THE CBF AND RARα, ASSOCIATED-FUSION PROTEINS AND NOVEL THERAPEUTIC APPROACHES

Remarkably, despite the structural and functional divergences among the fusion partners of the CBF and the RARα, the fusion proteins exploit similar, if not identical biochemical mechanisms to exert their dominant inhibitory efforts. The recruitment of corepressors and HDACs accompanied by some epigenetic changes such as hypermethylation of the promoters result in effective inhibition of gene expression [97Grimwade D, LoCoco F. Acute promyelocytic leukemia a model for the role of molecular diagnosis and residual disease monitoring in directing treatment approach in acute myeloid leukemia Leukemia 2002; 16: 1959-73.]. It has been established that the AML1/ETO chimeric protein interacts with corepressors including N-CoR, mSin3A and HDACs [4Kurokawa M, Hirai H. Role of AML1/Runx1 in the pathogenesis of hematological malignancies Cancer Sci 2003; 94: 841-6., 21Perry C, Eldor A, Soreq H. Runx1/AML1 in leukemia disrupted association with diverse protein partners Leuk Res 2002; 26: 221-8., 51Lutterbach B, Westendorf JJ, Linggi B, et al. ETO a target of t(8,21) in acute leukemia interacts with the N-CoR and mSin3 corepressors Mol Cell Biol 1998; 18: 7176-84., 109Lausen J, Cho S, Liu S, et al. The nuclear receptor co-repressor (N-CoR) utilizes repression domains I and III for interaction and co-repression with ETO J Biol Chem 2004; 279: 49281-8.-111Hildebrand D, Tiefenbach J, Heinzel T, et al. Multiple regions of ETO cooperate in transcriptional repression J Biol Chem 2001; 276: 9889-5.]. The ETO part of the chimeric protein is responsible for the recruitment of the corepressors [4Kurokawa M, Hirai H. Role of AML1/Runx1 in the pathogenesis of hematological malignancies Cancer Sci 2003; 94: 841-6., 43Mulloy JC, Cammenga J, MacKenzie KL, et al. The AML1-ETO fusion protein promotes the expansion of human hematopoietic stem cells Blood 2002; 99: 15-23., 54Hiebert SW, Lutterbach B, Amann J. Role of co-repressors in transcriptional repression mediated by the t(8,21) t(16,21) t(12,21) and inv(16) fusion proteins Curr Opin Hematol 2001; 8: 197-200., 113He LZ, Tolentino T, Grayson P, et al. Histone deacetylase inhibitors induce remission in transgenic models of therapy-resistant acute promyelocytic leukemia J Clin Invest 2001; 108: 1321-30.]. The RARα/fusion proteins also recruit corepressors and HADC-complexes in order to repress the genes that are normally activated by RARα [83Mistry AR, Pedersen EW, Solomon E, et al. The molecular pathogenesis of acute promyelocytic leukaemia implications for the clinical management of the disease Blood Rev 2003; 17: 71-97., 110Minucci S, Maccarana M, Cioce M. Oligomerization of RAR and AML1 transcription factors as a novel mechanism of oncogenic activation Mol Cell 2000; 5(5): 811-20.]. In deed, it has been demonstrated that the RARα fusion proteins recruits N-CoR and HDAC3 [108Atsumi A, Tomita A, Kiyoi H, et al. Histone deacetylase 3 (HDAC3) is recruited to target promoters by PML-RAR a as a component of the N-CoR co-repressor complex to repress transcription in vivo Biochem Biophys Res Commun 2006; 345: 1471-80.]. The PML/RARα fusion protein in particular recruits N-CoR/Sin3/HDAC1 complex to RARα-target promoter regions and inhibits transcription [68Berman JN, Look AT. Targeting transcription factors in acute leukemia in children Curr Drug Targets 2007; 8: 727-37.]. These unifying themes of the diverse subtypes of leukemia may offer the opportunity for designing a single treatment agent that can specifically target the leukemic cells and improve therapeutic efficacy compared to the classical chemotherapy. The CBF leukemias and the RARα-targeting APL all exploit similar biochemical mechanisms including recruitment of HDACs to the promoter region of the genes that play crucial roles in hematopoiesis [33Asou N. The role of a Runt domain transcription factor AML1/RUNX1 in leukemogenesis and its clinical implications Crit Rev Oncol Hematol 2003; 45: 129-50.]. Usage of HDAC inhibitors is underway in research laboratories and shows some promising results [117Liu S, Klisovic RB, Vukosavljevic T, et al. Targeting AML1/ETO-histone deacetylase repressor complex a novel mechanism for valproic acid-mediated gene expression and cellular differentiation in AML1/ETO-positive acute myeloid leukemia cells J Pharmacol Exp Ther 2007; 321: 953-60.]. For instance, treatment of leukemia cell lines with valproic acid (VPA) has shown encouraging results [117Liu S, Klisovic RB, Vukosavljevic T, et al. Targeting AML1/ETO-histone deacetylase repressor complex a novel mechanism for valproic acid-mediated gene expression and cellular differentiation in AML1/ETO-positive acute myeloid leukemia cells J Pharmacol Exp Ther 2007; 321: 953-60.]. VPA is known to selectively inhibit some HDACs. Treatment of cell lines that harbor AML1/ETO with VPA resulted in inhibition of the recruitment of HDACs by AML1/ETO and induced histone hyperacety-lation, which resulted in re-expression of the AML1/ETO repressed genes [117Liu S, Klisovic RB, Vukosavljevic T, et al. Targeting AML1/ETO-histone deacetylase repressor complex a novel mechanism for valproic acid-mediated gene expression and cellular differentiation in AML1/ETO-positive acute myeloid leukemia cells J Pharmacol Exp Ther 2007; 321: 953-60.]. HDAC inhibitors are not as dangerous as chemotherapy because they exert their therapeutic effects at the epigenetic level, and therefore can offer milder yet effective treatment choice.

Molecular and gene targeting therapeutic approaches have been tested. Specific protein redirection as a transcriptional therapy approach for t(8;21) has been attempted [118Steffen B, Serve H, Berdel WE, et al. Specific protein redirection as a transcriptional therapy approach for t(8,21) leukemia Proc Natl Acad Sci USA 2003; 100: 8448-53.]. In another study, overexpression of the domains of the fusion proteins that recruit corepressors has been attempted in cell lines that harbor the leukemic fusion genes [119Racanicchi S, Maccherani C, Liberatore C, et al. Targeting fusion protein/corepressor contact restores differentiation response in leukemia cells EMBO J 2005; 24: 1232-42.]. In the protein redirection approach, it was intended to remove the fusion proteins such as the AML1/ETO form the AML1-regulated gene promoters. Epigenetic therapy combined with some molecular targeting methodologies might offer safer and more effective therapeutic choice in the future.

FUTURE PERSPECTIVE

Genome-wide studies have allowed identification and further classification of risk groups and subtypes of AML. Gene-expression profiling allows a comprehensive classification of AML that includes previously identified genetically defined subgroups and a novel cluster with an adverse prognosis [120Valk PJ, Verhaak RG, Beijen MA, et al. Prognostically useful gene-expression profiles in acute myeloid leukemia N Engl J Med 2004; 350: 1617-28.]. A unique cluster with a distinctive gene-expression signature included cases of AML with a poor treatment outcome has been identified [121Dombret H, Preudhomme C, Boissel N. Core binding factor acute myeloid leukemia (CBF-AML) is high-dose Ara-C (HDAC) consolidation as effective as you think Curr Opin Hematol 2009; 16: 92-7.]. The biological and prognostic heterogeneity of CBF-AML subtypes, including gene mutation and gene expression profiles as well as molecular response to therapy needed to be further studied. The future studies to address the heterogeneity and sub-risk group of CBF-AML will help to design a unique predefined strategy to treat these patients. Prognostic significance of microRNA expression signatures associated with, for example, CEBPA mutations in cytogenetically normal acute myeloid leukemia with high-risk molecular features have been investigated [122Marcucci G, Maharry K, Radmacher MD, et al. Prognostic significance of, and gene and microRNA expression signatures associated with CEBPA mutations in cytogenetically normal acute myeloid leukemia with high-risk molecular features a Cancer and Leukemia Group B Study J Clin Oncol 2008; 26: 5078-87.]. More comprehensive gene-expression signature-based and microRNA expression-based classifiers are needed for predicting outcome for individual patients with greater accuracy in the future diagnostics. This information is likely to have a major impact on the clinical management of in selection of appropriate treatment, since many of the identified genetic alterations already constitute or will potentially become targets for specific therapeutic intervention. The molecular effects induced by chemotherapeutic agents such as panobinostat and doxorubicin have been investigated by analyzing gene expression, cell cycle, apoptosis and signaling pathways. Analyses of gene expression profiles identified many genes whose expression was exclusively affected by the combination of panobinostat and doxorubicin [123Maiso P, Colado E, Ocio EM. The synergy of panobinostat plus doxorubicin in acute myeloid leukemia suggests a role for HDAC inhibitors in the control of DNA repair Leukemia 2009; 8 [Epub ahead of print]]. Molecular cytology and pathology will have a great future impact on the precise classification of subtypes of leukemia and define the risk groups for diagnostics and prognostics and treatment respond. These novel approaches will help clinicians to design unique strategies to treat individual patients and to minimize the side-effects.

ACKNOWLEDGEMENTS

JLP was funded by the Swedish Cancer Society, the Swedish Children Foundation, The Swedish National Research Council, Malmö Hospital Cancer Foundation, Malmö Hospital Foundation, Crafoord Foundation and Gunnar Nilsson Cancer Foundation.

REFERENCES

[1] Lutz PG, Moog-Lutz C, Cayre YE. Signaling revisited in acute promyelocytic leukemia Leukemia 2002; 16: 1933-9.
[2] Speck NA, Gilliland DG. Core-binding factors in haematopoiesis and leukaemia Nat Rev Cancer 2002; 2: 502-13.
[3] Skalnik DG. Transcriptional mechanisms regulating myeloid-specific genes Gene 2002; 284: 1-21.
[4] Kurokawa M, Hirai H. Role of AML1/Runx1 in the pathogenesis of hematological malignancies Cancer Sci 2003; 94: 841-6.
[5] Ichikawa M, Asai T, Saito T, et al. AML-1 is required for megakaryocytic maturation and lymphocytic differentiation but not for maintenance of hematopoietic stem cells in adult hematopoiesis Nat Med 2004; 10: 299-304.
[6] Alcalay M, Orleth A, Sebastiani C, et al. Common themes in the pathogenesis of acute myeloid leukemia Oncogene 2001; 20: 5680-94.
[7] Look AT. Oncogenic transcription factors in the human acute leukemias Science 1997; 278: 1059-64.
[8] Wildonger J, Mann RS. The t(8,21) translocation converts AML1 into a constitutive transcriptional repressor Development 2005; 132: 2263-72.
[9] Barseguian K, Lutterbach B, Hiebert SW, et al. Multiple subnuclear targeting signals of the leukemia-related AML1/ETO and ETO repressor proteins Proc Natl Acad Sci USA 2002; 99: 15434-9.
[10] Bruserud O, Gjertsen BT, Huang T. Induction of differentiation and apoptosis- a possible strategy in the treatment of adult acute myelogenous leukemia Oncologist 2000; 5: 454-62.
[11] Bacher U, Kern W, Schnittger S, et al. Correlations of morphology according to FAB and WHO classification to cytogenetics in de novo acute myeloid leukemia a study on 2,235 patients Ann Hematol 2005; 84: 785-91.
[12] Burmeister T, Thiel E. Molecular genetics in acute and chronic leukemias J Cancer Res Clin Oncol 2001; 127: 80-90.
[13] Cripe LD. Adult acute leukemia Curr Probl Cancer 1997; 21: 1-64.
[14] McKenna RW. Multifaceted approach to the diagnosis and classification of acute leukemias Clin Chem 2000; 46: 1252-9.
[15] Kalantry S, Delva L, Gaboli M, et al. Gene rearrangements in the molecular pathogenesis of acute promyelocytic leukemia J Cell Physiol 1997; 173: 288-96.
[16] Niebuhr B, Fischer M, Täger M, et al. Gatekeeper function of the RUNX1 transcription factor in acute leukemia Blood Cells Mol Dis 2008; 40: 211-8.
[17] Stone RM, O'Donnell MR, Sekeres MA, et al. Acute myeloid leukemia Hematology (Am Soc Hematol Educ Prog) 2004; 00: 98-117.
[18] Okuda T, vanDeursen J, Hiebert SW. AML1 the target of multiple chromosomal translocations in human leukemia is essential for normal fetal liver hematopoiesis Cell 1996; 84: 321-0.
[19] Melnick A, Carlile GW, McConnell MJ, et al. AML-1/ETO fusion protein is a dominant negative inhibitor of transcriptional repression by the promyelocytic leukemia zinc finger protein Blood 2000; 96: 3939-47.
[20] Licht JD. AML1 and the AML1-ETO fusion protein in the pathogenesis of t(8,21) AML Oncogene 2001; 20: 5660-79.
[21] Perry C, Eldor A, Soreq H. Runx1/AML1 in leukemia disrupted association with diverse protein partners Leuk Res 2002; 26: 221-8.
[22] Li X, Vradii D, Gutierrez S, et al. Subnuclear targeting of Runx1 is required for synergistic activation of the myeloid specific M-CSF receptor promoter by PU J Cell Biochem 2005; 96: 795-809.
[23] Petrovick MS, Hiebert SW, Friedman AD, et al. Multiple functional domains of AML1 PU1 and C/EBPa synergize with different regions of AML1 Mol Cell Biol 1998; 18: 3915-25.
[24] Ma SK, Wan TS, Chan LC. Cytogenetics and molecular genetics of childhood leukemia Hematol Oncol 1999; 17: 91-105.
[25] Reilly JT. Pathogenesis of acute myeloid leukaemia and inv(16)(p13,q22) a paradigm for understanding leukaemogenesis Br J Haematol 2005; 128: 18-34.
[26] Kundu M, Liu PP. Function of the inv(16) fusion gene CBFb-MYH11 Curr Opin Hematol 2001; 8: 201-5.
[27] Licht JD, Sternberg DW. The molecular pathology of acute myeloid leukemia Hematology (Am Soc Hematol Educ Prog) 2005; 00: 137-42.
[28] Krug U, Ganser A, Koeffler HP. Tumor suppressor genes in normal and malignant hematopoiesis Oncogene 2002; 21: 3475-95.
[29] Zhang L, Lukasik SM, Speck NA, et al. Structural and functional characterization of Runx1 CBFb and CBF b-SMMHC Blood Cells Mol Dis 2003; 30: 147-56.
[30] Adya N, Stacy T, Speck NA, et al. The leukemic protein core binding factor b (CBFb)-smooth-muscle myosin heavy chain sequesters CBF a 2 into cytoskeletal filaments and aggregates Mol Cell Biol 1998; 18: 7432-43.
[31] Downing JR. The AML1-ETO chimaeric transcription factor in acute myeloid leukaemia: biology and clinical significance Br J Haematol 1999; 106: 296-308.
[32] Lukasik SM, Zhang L, Corpora T, et al. Altered affinity of CBF β-SMMHC for Runx1 explains its role in leukemogenesis Nat Struct Biol 2002; 9: 674-9.
[33] Asou N. The role of a Runt domain transcription factor AML1/RUNX1 in leukemogenesis and its clinical implications Crit Rev Oncol Hematol 2003; 45: 129-50.
[34] Kundu M, Chen A, Anderson S, et al. Role of CBFb in hematopoiesis and perturbations resulting from expression of the leukemogenic fusion gene CBFb -MYH11 Blood 2002; 100: 2449-56.
[35] Castilla LH, Wijmenga C, Wang Q, et al. Failure of embryonic hematopoiesis and lethal hemorrhages in mouse embryos heterozygous for a knocked-in leukemia gene CBFb-MYH11 Cell 1996; 87: 687-96.
[36] Hart SM, Foroni L. Core binding factor genes and human leukemia Haematologica 2002; 87: 1307-23.
[37] Scandura JM, Boccuni P, Cammenga J, et al. Transcription factor fusions in acute leukemia variations on a theme Oncogene 2002; 21: 3422-44.
[38] Wang Q, Stacy T, Miller JD, et al. The CBFb subunit is essential for CBF a 2 (AML1) function in vivo Cell 1996; 87: 697-708.
[39] Gilliland DG, Jordan CT, Felix CA. The molecular basis of leukemia Hematology (Am Soc Hematol Educ Prog) 2004; 00: 80-97.
[40] Yokomizo T, Ogawa M, Osato M, et al. Requirement of Runx1/AML1/PEBP2aB for the generation of haematopoietic cells from endothelial cells Genes Cells 2001; 6: 13-23.
[41] Ito Y. Oncogenic potential of the RUNX gene family overview Oncogene 2004; 23: 4198-208.
[42] Levanon D, Groner Y. Structure and regulated expression of mammalian RUNX genes Oncogene 2004; 23: 4211-9.
[43] Mulloy JC, Cammenga J, MacKenzie KL, et al. The AML1-ETO fusion protein promotes the expansion of human hematopoietic stem cells Blood 2002; 99: 15-23.
[44] Tonks A, Pearn L, Tonks AJ, et al. The AML1-ETO fusion gene promotes extensive self-renewal of human primary erythroid cells Blood 2003; 101: 624-32.
[45] Miyoshi H, Shimizu K, Kozu T, et al. Ohki M t (821) breakpoints on chromosome 21 in acute myeloid leukemia are clustered within a limited region of a single gene AML1 Proc Natl Acad Sci USA 1991; 88: 10431-4.
[46] Yuan Y, Zhou L, Miyamoto T, et al. AML1-ETO expression is directly involved in the development of acute myeloid leukemia in the presence of additional mutations Proc Natl Acad Sci USA 2001; 98: 10398-403.
[47] Linggi B, Müller-Tidow C, vandeLocht L, et al. The t (8,21) fusion protein AML1 ETO specifically represses the transcription of the p14(ARF) tumor suppressor in acute myeloid leukemia Nat Med 2002; 8: 743-50.
[48] Meyers S, Lenny N, Hiebert SW. The t(8,21) fusion protein interferes with AML-1B-dependent transcriptional activation Mol Cell Biol 1995; 15: 1974-82.
[49] Meyers S, Downing JR, Hiebert SW. Identification of AML-1 and the (8,21) translocation protein (AML-1/ETO) as sequence-specific DNA-binding proteins the runt homology domain is required for DNA binding and protein-protein interactions Mol Cell Biol 1993; 13: 6336-45.
[50] LoCoco F, Pisegna S, Diverio D. The AML1 gene a transcription factor involved in the pathogenesis of myeloid and lymphoid leukemias Haematologica 1997; 82: 364-70.
[51] Lutterbach B, Westendorf JJ, Linggi B, et al. ETO a target of t(8,21) in acute leukemia interacts with the N-CoR and mSin3 corepressors Mol Cell Biol 1998; 18: 7176-84.
[52] Yergeau DA, Hetherington CJ, Wang Q, et al. Embryonic lethality and impairment of haematopoiesis in mice heterozygous for an AML1-ETO fusion gene Nat Genet 1997; 15: 303-6.
[53] Vangala RK, Heiss-Neumann MS, Rangatia JS, et al. The myeloid master regulator transcription factor PU is inactivated by AML1-ETO i t(8; 1) myeloid leukemia. Blood 2003, 101: 270-7.
[54] Hiebert SW, Lutterbach B, Amann J. Role of co-repressors in transcriptional repression mediated by the t(8,21) t(16,21) t(12,21) and inv(16) fusion proteins Curr Opin Hematol 2001; 8: 197-200.
[55] Peterson LF, Lo MC, Okumura AJ, et al. Inability of RUNX1/AML1 to breach AML1-ETO block of embryonic stem cell definitive hematopoiesis Blood Cells Mol Dis 2007; 39: 321-8.
[56] Follows GA, Tagoh H, Lefevre P, et al. Epigenetic consequences of AML1-ETO action at the human c-FMS locus EMBO J 2003; 22: 2798-809.
[57] Mandelli F, Petti MC, LoCoco F. Therapy of acute myeloid leukemia towards a patient-oriented risk-adapted approach Haematologica 1998; 83: 1015-23.
[58] Nishida S, Hosen N, Shirakata T, et al. AML1-ETO rapidly induces acute myeloblastic leukemia in cooperation with the Wilms tumor gene WT1 Blood 2006; 107: 3303-12.
[59] Poirel H, Radford-Weiss I, Rack K, et al. Detection of the chromosome 16 CBF b-MYH11 fusion transcript in myelomono-cytic leukemias Blood 1995; 85: 1313-22.
[60] Marlton P, Claxton DF, Liu P, et al. Molecular characterization of 16p deletions associated with inversion 16 defines the critical fusion for leukemogenesis Blood 1995; 85: 772-9.
[61] Liu P, Tarlé SA, Hajra A, et al. Fusion between transcription factor CBFb/PEBP2b and a myosin heavy chain in acute myeloid leukemia Science 1993; 261: 1041-4.
[62] Huang G, Shigesada K, Wee HJ, et al. Molecular basis for a dominant inactivation of RUNX1/AML1 by the leukemogenic inversion 16 chimera Blood 2004; 103: 3200-7.
[63] Tanaka Y, Fujii M, Hayashi K, et al. The chimeric protein PEBP2 b/CBF b-SMMHC disorganizes cytoplasmic stress fibers and inhibits transcriptional activation Oncogene 1998; 17: 699-708.
[64] Durst KL, Lutterbach B, Kummalue T, et al. The inv(16) fusion protein associates with corepressors via a smooth muscle myosin heavy-chain domain Mol Cell Biol 2003; 23: 607-19.
[65] Shurtleff SA, Meyers S, Hiebert SW, et al. Heterogeneity in CBF b/MYH11 fusion messages encoded by the inv(16)(p13q22) and the t(16,16)(p13,q22) in acute myelogenous leukemia Blood 1995; 85: 3695-703.
[66] Cao W, Adya N, Britos-Bray M, et al. The core binding factor (CBF) a interaction domain and the smooth muscle myosin heavy chain (SMMHC) segment of CBFb-SMMHC are both required to slow cell proliferation J Biol Chem 1998; 273: 31534-40.
[67] Shigesada K, vandeSluis B, Liu PP. Mechanism of leukemogenesis by the inv(16) chimeric gene CBFb/PEBP2b-MHY11 Oncogene 2004; 23: 4297-307.
[68] Berman JN, Look AT. Targeting transcription factors in acute leukemia in children Curr Drug Targets 2007; 8: 727-37.
[69] Liu PP, Hajra A, Wijmenga C, et al. Molecular pathogenesis of the chromosome 16 inversion in the M4Eo subtype of acute myeloid leukemia Blood 1995; 85: 2289-302.
[70] Schnittger S, Bacher U, Haferlach C. Rare CBFB-MYH11 fusion transcripts in AML with inv(16)/t(16,16) are associated with therapy-related AML M4eo atypical cytomorphology atypical immunophenotype, atypical additional chromosomal rearrange-ments and low white blood cell count a study on 162 patients Leukemia 2007; 21: 725-31.
[71] Lutterbach B, Hou Y, Durst KL. The inv(16) encodes an acute myeloid leukemia 1 transcriptional corepressor Proc Natl Acad Sci USA 1999; 96: 12822-7.
[72] Castilla LH, Garrett L, Adya N. The fusion gene CBFb-MYH11 blocks myeloid differentiation and predisposes mice to acute myelomonocytic leukaemia Nat Genet 1999; 23: 144-6.
[73] Britos-Bray M, Ramirez M, Cao W, et al. CBFb-SMMHC expressed in M4eo acute myeloid leukemia reduces p53 induction and slows apoptosis in hematopoietic cells exposed to DNA-damaging agents Blood 1998; 92: 4344-52.
[74] Kummalue T, Lou J, Friedman AD. Multimerization via its myosin domain facilitates nuclear localization and inhibition of core binding factor (CBF) activities by the CBFb-smooth muscle myosin heavy chain myeloid leukemia oncoprotein Mol Cell Biol 2002; 22: 8278-91.
[75] Kanno Y, Kanno T, Sakakura C, et al. Cytoplasmic sequestration of the polyomavirus enhancer binding protein 2 (PEBP2)/core binding factor a (CBF a) subunit by the leukemia-related PEBP2/CBFb-SMMHC fusion protein inhibits PEBP2/CBF-mediated transactivation Mol Cell Biol 1998; 18: 4252-61.
[76] Zent CS, Mathieu C, Claxton DF, et al. The chimeric genes AML1/MDS1 and AML1/EAP inhibit AML1B activation at the CSF1R promoter, but only AML1/MDS1 has tumor-promoter properties Proc Natl Acad Sci USA 1996; 93: 1044-8.
[77] Yin CC, Cortes J, Barkoh B, et al. t(3,21)(q26,q22) in myeloid leukemia an aggressive syndrome of blast transformation associated with hydroxyurea or antimetabolite therapy Cancer 2006; 106: 1730-8.
[78] Kurokawa M, Mitani K, Imai Y, et al. The t(3,21) fusion product AML1/Evi-1 interacts with Smad3 and blocks transforming growth factor-b-mediated growth inhibition of myeloid cells Blood 1998; 92: 4003-12.
[79] Tanaka T, Mitani K, Kurokawa M, et al. Dual functions of the AML1/Evi-1 chimeric protein in the mechanism of leukemogenesis in t(3,21) leukemias Mol Cell Biol 1995; 15: 2383-92.
[80] Kurokawa M, Mitani K, Irie K, et al. The oncoprotein Evi-1 represses TGF-b signalling by inhibiting Smad3 Nature 1998; 394: 92-6.
[81] Douer D. Transcription therapy for acute promyelocytic leukaemia Expert Opin Investig Drugs 2000; 9: 329-46.
[82] Chambon PA. Decade of molecular biology of retinoic acid receptors FASEB J 1996; 10: 940-54.
[83] Mistry AR, Pedersen EW, Solomon E, et al. The molecular pathogenesis of acute promyelocytic leukaemia implications for the clinical management of the disease Blood Rev 2003; 17: 71-97.
[84] Melnick A, Licht JD. Deconstructing a disease RAR a its fusion partners and their roles in the pathogenesis of acute promyelocytic leukemia Blood 1999; 93: 3167-215.
[85] Fontana JA, Rishi AK. Classical and novel retinoids their targets in cancer therapy Leukemia 2002; 16: 463-72.
[86] Drumea K, Yang ZF, Rosmarin A. Retinoic acid signaling in myelopoiesis Curr Opin Hematol 2008; 15: 37-41.
[87] Lefebvre B, Brand C, Lefebvre P, et al. Chromosomal integration of retinoic acid response elements prevents cooperative transcriptional activation by retinoic acid receptor and retinoid X receptor Mol Cell Biol 2002; 22: 1446-59.
[88] Collins SJ. The role of retinoids and retinoic acid receptors in normal hematopoiesis Leukemia 2002; 16: 1896-905.
[89] Gratas C, Menot ML, Dresch C, et al. Retinoid acid supports granulocytic but not erythroid differentiation of myeloid progenitors in normal bone marrow cells Leukemia 1993; 7: 1156-62.
[90] Tocci A, Parolini I, Gabbianelli M. Dual action of retinoic acid on human embryonic/fetal hematopoiesis blockade of primitive progenitor proliferation and shift from multipotent/eryth-roid/monocytic to granulocytic differentiation program Blood 1996; 88: 2878-88.
[91] Duprez E, Wagner K, Koch H, et al. C/EBPb a major PML-RARa-responsive gene in retinoic acid-induced differentiation of APL cells EMBO J 2003; 22: 5806-16.
[92] Merghoub T, Gurrieri C, Piazza F. Modeling acute promye-locytic leukemia in the mouse new insights in the pathogenesis of human leukemias Blood Cells Mol Dis 2001; 27: 231-48.
[93] He LZ, Merghoub T, Pandolfi PP. In vivo analysis of the mole-cular pathogenesis of acute promyelocytic leukemia in the mouse and its therapeutic implications Oncogene 1999; 18: 5278-92.
[94] Meani N, Minardi S, Licciulli S, et al. Molecular signature of retinoic acid treatment in acute promyelocytic leukemia Oncogene 2005; 24: 3358-68.
[95] Hummel JL, Zhang T, Wells RA, et al. The retinoic acid receptor a (RAR a) chimeric proteins PML- PLZF- NPM- and NuMA-RAR a have distinct intracellular localization patterns Cell Growth Differ 2002; 13: 173-83.
[96] Rego EM, Ruggero D, Tribioli C, et al. Leukemia with distinct phenotypes in transgenic mice expressing PML/RAR a PLZF/RAR a or NPM/RAR a Oncogene 2006; 25: 1974-9.
[97] Grimwade D, LoCoco F. Acute promyelocytic leukemia a model for the role of molecular diagnosis and residual disease monitoring in directing treatment approach in acute myeloid leukemia Leukemia 2002; 16: 1959-73.
[98] Pandolfi PP. Oncogenes and tumor suppressors in the molecular pathogenesis of acute promyelocytic leukemia Hum Mol Genet 2001; 10: 769-5.
[99] deThé H, Chomienne C, Lanotte M, et al. The t(15,17) translocation of acute promyelocytic leukaemia fuses the retinoic acid receptor a gene to a novel transcribed locus Nature 1990; 347: 558-61.
[100] He LZ, Tribioli C, Rivi R, et al. Acute leukemia with promyelocytic features in PML/RAR a transgenic mice Proc Natl Acad Sci USA 1997; 94: 5302-7.
[101] Koken MH, Reid A, Quignon F, et al. Leukemia-associated retinoic acid receptor a fusion partners PML and PLZF heterodimerize and colocalize to nuclear bodies Proc Natl Acad Sci USA 1997; 94: 10255-60.
[102] Rego EM, He LZ, Warrell RPJr, et al. Retinoic acid (RA) and As2O3 treatment in transgenic models of acute promyelocytic leukemia (APL) unravel the distinct nature of the leukemogenic process induced by the PML-RAR a and PLZF-RAR a oncoproteins Proc Natl Acad Sci USA 2000; 97: 10173-8.
[103] Chen SJ, Zelent A, Tong JH, et al. Rearrangements of the retinoic acid receptor a and promyelocytic leukemia zinc finger genes resulting from t(11,17)(q23,q21) in a patient with acute promyelocytic leukemia J Clin Invest 1993; 91: 2260-7.
[104] Chen Z, Brand NJ, Chen A, et al. Fusion between a novel Kruppel-like zinc finger gene and the retinoic acid receptor- a locus due to a variant t(11,17) translocation associated with acute promyelocytic leukaemia EMBO J 1993; 12: 1161-7.
[105] Colombo E, Marine JC, Danovi D, et al. Nucleophosmin regulates the stability and transcriptional activity of p53 Nat Cell Biol 2002; 4: 529-33.
[106] Hsu HL, Yeh NH. Dynamic changes of NuMA during the cell cycle and possible appearance of a truncated form of NuMA during apoptosis J Cell Sci 1996; 109: 277-88.
[107] Dionne MA, Howard L, Compton DA. NuMA is a component of an insoluble matrix at mitotic spindle poles Cell Motil Cytoskeleton 1999; 42: 189-203.
[108] Atsumi A, Tomita A, Kiyoi H, et al. Histone deacetylase 3 (HDAC3) is recruited to target promoters by PML-RAR a as a component of the N-CoR co-repressor complex to repress transcription in vivo Biochem Biophys Res Commun 2006; 345: 1471-80.
[109] Lausen J, Cho S, Liu S, et al. The nuclear receptor co-repressor (N-CoR) utilizes repression domains I and III for interaction and co-repression with ETO J Biol Chem 2004; 279: 49281-8.
[110] Minucci S, Maccarana M, Cioce M. Oligomerization of RAR and AML1 transcription factors as a novel mechanism of oncogenic activation Mol Cell 2000; 5(5): 811-20.
[111] Hildebrand D, Tiefenbach J, Heinzel T, et al. Multiple regions of ETO cooperate in transcriptional repression J Biol Chem 2001; 276: 9889-5.
[112] Amann JM, Nip J, Strom DK, et al. ETO a target of t(8,21) in acute leukemia makes distinct contacts with multiple histone deacetylases and binds mSin3A through its oligomerization domain Mol Cell Biol 2001; 21: 6470-83.
[113] He LZ, Tolentino T, Grayson P, et al. Histone deacetylase inhibitors induce remission in transgenic models of therapy-resistant acute promyelocytic leukemia J Clin Invest 2001; 108: 1321-30.
[114] Guidez F, Ivins S, Zhu J, et al. Reduced retinoic acid-sensitivities of nuclear receptor corepressor binding to PML- and PLZF-RAR a underlie molecular pathogenesis and treatment of acute promyelocytic leukemia Blood 1998; 91: 2634-42.
[115] Glasow A, Prodromou N, Xu K, et al. Retinoids and myelomonocytic growth factors cooperatively activate RARa and induce human myeloid leukemia cell differentiation via MAP kinase pathways Blood 2005; 105: 341-9.
[116] Pitha-Rowe I, Petty WJ, Kitareewan S, et al. Retinoid target genes in acute promyelocytic leukemia Leukemia 2003; 17: 1723-30.
[117] Liu S, Klisovic RB, Vukosavljevic T, et al. Targeting AML1/ETO-histone deacetylase repressor complex a novel mechanism for valproic acid-mediated gene expression and cellular differentiation in AML1/ETO-positive acute myeloid leukemia cells J Pharmacol Exp Ther 2007; 321: 953-60.
[118] Steffen B, Serve H, Berdel WE, et al. Specific protein redirection as a transcriptional therapy approach for t(8,21) leukemia Proc Natl Acad Sci USA 2003; 100: 8448-53.
[119] Racanicchi S, Maccherani C, Liberatore C, et al. Targeting fusion protein/corepressor contact restores differentiation response in leukemia cells EMBO J 2005; 24: 1232-42.
[120] Valk PJ, Verhaak RG, Beijen MA, et al. Prognostically useful gene-expression profiles in acute myeloid leukemia N Engl J Med 2004; 350: 1617-28.
[121] Dombret H, Preudhomme C, Boissel N. Core binding factor acute myeloid leukemia (CBF-AML) is high-dose Ara-C (HDAC) consolidation as effective as you think Curr Opin Hematol 2009; 16: 92-7.
[122] Marcucci G, Maharry K, Radmacher MD, et al. Prognostic significance of, and gene and microRNA expression signatures associated with CEBPA mutations in cytogenetically normal acute myeloid leukemia with high-risk molecular features a Cancer and Leukemia Group B Study J Clin Oncol 2008; 26: 5078-87.
[123] Maiso P, Colado E, Ocio EM. The synergy of panobinostat plus doxorubicin in acute myeloid leukemia suggests a role for HDAC inhibitors in the control of DNA repair Leukemia 2009; 8 [Epub ahead of print]
Track Your Manuscript:


Endorsements



"Open access will revolutionize 21st century knowledge work and accelerate the diffusion of ideas and evidence that support just in time learning and the evolution of thinking in a number of disciplines."


Daniel Pesut
(Indiana University School of Nursing, USA)

"It is important that students and researchers from all over the world can have easy access to relevant, high-standard and timely scientific information. This is exactly what Open Access Journals provide and this is the reason why I support this endeavor."


Jacques Descotes
(Centre Antipoison-Centre de Pharmacovigilance, France)

"Publishing research articles is the key for future scientific progress. Open Access publishing is therefore of utmost importance for wider dissemination of information, and will help serving the best interest of the scientific community."


Patrice Talaga
(UCB S.A., Belgium)

"Open access journals are a novel concept in the medical literature. They offer accessible information to a wide variety of individuals, including physicians, medical students, clinical investigators, and the general public. They are an outstanding source of medical and scientific information."


Jeffrey M. Weinberg
(St. Luke's-Roosevelt Hospital Center, USA)

"Open access journals are extremely useful for graduate students, investigators and all other interested persons to read important scientific articles and subscribe scientific journals. Indeed, the research articles span a wide range of area and of high quality. This is specially a must for researchers belonging to institutions with limited library facility and funding to subscribe scientific journals."


Debomoy K. Lahiri
(Indiana University School of Medicine, USA)

"Open access journals represent a major break-through in publishing. They provide easy access to the latest research on a wide variety of issues. Relevant and timely articles are made available in a fraction of the time taken by more conventional publishers. Articles are of uniformly high quality and written by the world's leading authorities."


Robert Looney
(Naval Postgraduate School, USA)

"Open access journals have transformed the way scientific data is published and disseminated: particularly, whilst ensuring a high quality standard and transparency in the editorial process, they have increased the access to the scientific literature by those researchers that have limited library support or that are working on small budgets."


Richard Reithinger
(Westat, USA)

"Not only do open access journals greatly improve the access to high quality information for scientists in the developing world, it also provides extra exposure for our papers."


J. Ferwerda
(University of Oxford, UK)

"Open Access 'Chemistry' Journals allow the dissemination of knowledge at your finger tips without paying for the scientific content."


Sean L. Kitson
(Almac Sciences, Northern Ireland)

"In principle, all scientific journals should have open access, as should be science itself. Open access journals are very helpful for students, researchers and the general public including people from institutions which do not have library or cannot afford to subscribe scientific journals. The articles are high standard and cover a wide area."


Hubert Wolterbeek
(Delft University of Technology, The Netherlands)

"The widest possible diffusion of information is critical for the advancement of science. In this perspective, open access journals are instrumental in fostering researches and achievements."


Alessandro Laviano
(Sapienza - University of Rome, Italy)

"Open access journals are very useful for all scientists as they can have quick information in the different fields of science."


Philippe Hernigou
(Paris University, France)

"There are many scientists who can not afford the rather expensive subscriptions to scientific journals. Open access journals offer a good alternative for free access to good quality scientific information."


Fidel Toldrá
(Instituto de Agroquimica y Tecnologia de Alimentos, Spain)

"Open access journals have become a fundamental tool for students, researchers, patients and the general public. Many people from institutions which do not have library or cannot afford to subscribe scientific journals benefit of them on a daily basis. The articles are among the best and cover most scientific areas."


M. Bendandi
(University Clinic of Navarre, Spain)

"These journals provide researchers with a platform for rapid, open access scientific communication. The articles are of high quality and broad scope."


Peter Chiba
(University of Vienna, Austria)

"Open access journals are probably one of the most important contributions to promote and diffuse science worldwide."


Jaime Sampaio
(University of Trás-os-Montes e Alto Douro, Portugal)

"Open access journals make up a new and rather revolutionary way to scientific publication. This option opens several quite interesting possibilities to disseminate openly and freely new knowledge and even to facilitate interpersonal communication among scientists."


Eduardo A. Castro
(INIFTA, Argentina)

"Open access journals are freely available online throughout the world, for you to read, download, copy, distribute, and use. The articles published in the open access journals are high quality and cover a wide range of fields."


Kenji Hashimoto
(Chiba University, Japan)

"Open Access journals offer an innovative and efficient way of publication for academics and professionals in a wide range of disciplines. The papers published are of high quality after rigorous peer review and they are Indexed in: major international databases. I read Open Access journals to keep abreast of the recent development in my field of study."


Daniel Shek
(Chinese University of Hong Kong, Hong Kong)

"It is a modern trend for publishers to establish open access journals. Researchers, faculty members, and students will be greatly benefited by the new journals of Bentham Science Publishers Ltd. in this category."


Jih Ru Hwu
(National Central University, Taiwan)


Browse Contents




Webmaster Contact: info@benthamopen.net
Copyright © 2022 Bentham Open