Research ArticleCancer

Combined targeting of BCL-2 and BCR-ABL tyrosine kinase eradicates chronic myeloid leukemia stem cells

Science Translational Medicine  07 Sep 2016:
Vol. 8, Issue 355, pp. 355ra117
DOI: 10.1126/scitranslmed.aag1180

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Stemming the regrowth of leukemia

Chronic myeloid leukemia is usually held up as the poster child for targeted therapy, given the success of imatinib and related compounds such as nilotinib in treating the disease. Unfortunately, even these drugs are not perfect because they do not eliminate cancer stem cells. As a result, patients have to remain on treatment indefinitely or else face a high likelihood of relapse. Carter et al. have discovered that the antiapoptotic protein BCL-2 plays a key role in the survival of chronic myeloid leukemia stem cells and that combined treatment with a BCL-2 inhibitor and nilotinib can successfully eradicate both the active tumor cells and the stem cells, suggesting the potential for curative treatment.

Abstract

BCR-ABL tyrosine kinase inhibitors (TKIs) are effective against chronic myeloid leukemia (CML), but they rarely eliminate CML stem cells. Disease relapse is common upon therapy cessation, even in patients with complete molecular responses. Furthermore, once CML progresses to blast crisis (BC), treatment outcomes are dismal. We hypothesized that concomitant targeting of BCL-2 and BCR-ABL tyrosine kinase could overcome these limitations. We demonstrate increased BCL-2 expression at the protein level in bone marrow cells, particularly in LinSca-1+cKit+ cells of inducible CML in mice, as determined by CyTOF mass cytometry. Further, selective inhibition of BCL-2, aided by TKI-mediated MCL-1 and BCL-XL inhibition, markedly decreased leukemic LinSca-1+cKit+ cell numbers and long-term stem cell frequency and prolonged survival in a murine CML model. Additionally, this combination effectively eradicated CD34+CD38, CD34+CD38+, and quiescent stem/progenitor CD34+ cells from BC CML patient samples. Our results suggest that BCL-2 is a key survival factor for CML stem/progenitor cells and that combined inhibition of BCL-2 and BCR-ABL tyrosine kinase has the potential to significantly improve depth of response and cure rates of chronic-phase and BC CML.

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