TY - JOUR
T1 - Combined targeting of BCL-2 and BCR-ABL tyrosine kinase eradicates chronic myeloid leukemia stem cells
AU - Carter, Bing Z.
AU - Mak, Po Yee
AU - Mu, Hong
AU - Zhou, Hongsheng
AU - Mak, Duncan H.
AU - Schober, Wendy
AU - Leverson, Joel D.
AU - Zhang, Bin
AU - Bhatia, Ravi
AU - Huang, Xuelin
AU - Cortes, Jorge
AU - Kantarjian, Hagop
AU - Konopleva, Marina
AU - Andreeff, Michael
N1 - Funding Information:
This work was supported in part by NIH grants P01CA49639 and P30CA016672 and the Paul and Mary Haas Chair in Genetics (to M.A.) and by research funding from AbbVie Inc. (to B.Z.C.).
PY - 2016/9/7
Y1 - 2016/9/7
N2 - 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 Lin-Sca-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 Lin-Sca-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.
AB - 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 Lin-Sca-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 Lin-Sca-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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U2 - 10.1126/scitranslmed.aag1180
DO - 10.1126/scitranslmed.aag1180
M3 - Article
C2 - 27605552
AN - SCOPUS:84988805216
SN - 1946-6234
VL - 8
JO - Science Translational Medicine
JF - Science Translational Medicine
IS - 355
M1 - 355ra117
ER -