BMS-214662 potently induces apoptosis of Chronic Myeloid Leukemia stem and progenitor cells and synergises with tyrosine kinas

Chronic myeloid leukemia (CML), a hematopoietic stem cell disorder, cannot be eradicated by conventional chemotherapy or the tyrosine kinase inhibitor (TKI) imatinib mesylate (IM). To target CML stem/progenitor cells we investigated BMS-214662, a cytotoxic farnesyltransferase inhibitor, previously reported to kill non-proliferating tumor cells. IM or dasatinib alone reversibly arrested proliferation of CML stem/progenitor cells without inducing apoptosis. In contrast, BMS-214662, alone or in combination with IM or dasatinib, potently induced apoptosis of both proliferating and quiescent CML stem/progenitor cells with <1% recovery of Philadelphia positive LTC-IC. Normal stem/progenitor cells were relatively spared by BMS-214662, suggesting selectivity for leukemic stem/progenitor cells. The ability to induce selective apoptosis of leukemic stem/progenitor cells was unique to BMS214662 and not seen with a structurally similar agent BMS-225975. BMS214662 was cytotoxic against CML blast crisis stem/progenitor cells, particularly in combination with a TKI and equally effective in cell lines harbouring wild-type versus mutant BCR-ABL, including the T315I mutation. This is the first report of an agent with activity in resistant and blast crisis CML that selectively kills CML stem/progenitor cells through apoptosis and offers potential for eradication of chronic phase CML. For personal use only. on October 28, 2017. by guest www.bloodjournal.org From