The BCR/ABL fusion protein is the hallmark of Philadelphia Chromosome positive (Ph+) leukemia. The
constitutive activation of the ABL-kinase in BCR/ABL cells induces the leukemic phenotype. Targeted inhibition of
BCR/ABL by small molecule inhibitors reverses the transformation potential of BCR/ABL. Recently, we definitively
proved that targeting the tetramerization of BCR/ABL mediated by the N-terminal coiled-coil domain (CC) using competitive
peptides, representing the helix-2 of the CC, represents a valid therapeutic approach for treating Ph+ leukemia.
To further develop competitive peptides for targeting BCR/ABL, we created a membrane permeable helix-2 peptide
(MPH-2) by fusing the helix-2 peptide with a peptide transduction tag. In this study, we report that the MPH-2:
(i) interacted with BCR/ABL in vivo; (ii) efficiently inhibited the autophosphorylation of BCR/ABL; (iii) suppressed
the growth and viability of Ph+ leukemic cells; and (iv) was efficiently transduced into mononuclear cells (MNC) in an
in vivo mouse model. This study provides the first evidence that an efficient peptide transduction system facilitates the employment of
competitive peptides to target the oligomerization interface of BCR/ABL in vivo.