Pan–BCL-2 Inhibition Sensitizes Leukemic Stem Cells to Kinase Inhibitors

Tyrosine kinase inhibitors (TKI) that target BCR–ABL eliminate the bulk of chronic myeloid leukemia (CML) cells but do not effectively eradicate quiescent leukemic stem cells (LSC) that can drive relapse and progression from chronic phase to blast crisis. Increased antiapoptotic BCL-2 family protein expression has been associated with leukemogenesis, TKI resistance, and stem cell survival, but because most studies have focused only on BCR–ABL-expressing cell lines the role of BCL-2 family members in LSC maintenance and TKI resistance in vivo remains unclear. Goff and colleagues analyzed BCL-2 family member expression in purified progenitor cells from primary normal, CML chronic phase, and CML blast crisis human samples and found that prosurvival BCL-2 family gene isoforms were globally upregulated in blast crisis LSCs. These LSCs caused blast crisis CML upon implantation into recipient mice and robustly engrafted into stem cell niches. Interestingly, quiescent LSCs were enriched in the bone marrow compared with other niches, and even though dasatinib treatment greatly reduced the leukemic burden and inhibited BCR–ABL activity in LSCs, a drug-resistant LSC population persisted in the bone marrow. Compared with LSCs from other tissues, bone marrow LSCs expressed markedly higher levels of BCL-2 and the prosurvival isoforms of MCL-1 and BFL-1, providing a rationale for testing the effect of sabutoclax, a small molecule that inhibits all prosurvival BCL-2 family proteins, on bone marrow LSC growth. In a stromal coculture system, sabutoclax significantly reduced LSC survival and self-renewal, whereas ABT-737, which only inhibits BCL-2 and BCL-XL, was not as effective. Furthermore, sabutoclax pretreatment sensitized LSCs to dasatinib, and combined treatment of marrow with sabutoclax and dasatinib significantly inhibited primary and serial LSC engraftment and prolonged survival. Pan–BCL-2 inhibition may therefore be useful in combination with TKI therapy to eradicate LSCs in protective niches that drive relapse and disease progression.

Goff DJ, Recart AC, Sadarangani A, Chun HJ, Barrett CL, Krajewska M, et al. A pan-BCL2 inhibitor renders bone-marrow-resident human leukemia cells sensitive to tyrosine kinase inhibition. Cell Stem Cell 2013 Jan 17 [Epub ahead of print].

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