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

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 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.

• Authors: Bing Z Carter, Po Yee Mak, Hong Mu, Hongsheng Zhou, Duncan H Mak, Wendy Schober, Joel D Leverson, Bin Zhang, Ravi Bhatia, Xuelin Huang, Jorge Cortes, Hagop Kantarjian, Marina Konopleva, Michael Andreeff
• Journal: Science translational medicine (Sci Transl Med) Vol. 8 Issue 355 Pg. 355ra117 (09 07 2016) ISSN: 1946-6242 [Electronic] United States
• PMID: 27605552 (Publication Type: Journal Article, Research Support, N.I.H., Extramural, Research Support, Non-U.S. Gov't)
• Copyright: Copyright © 2016, American Association for the Advancement of Science.

Chemical References

• Antigens, CD34
• Protein Kinase Inhibitors
• Proto-Oncogene Proteins c-bcl-2
• Fusion Proteins, bcr-abl

Topics

• Animals
• Antigens, CD34 (metabolism)
• Apoptosis (drug effects)
• Blast Crisis (drug therapy, pathology)
• Cell Cycle (drug effects)
• Cell Proliferation (drug effects)
• Fusion Proteins, bcr-abl (antagonists & inhibitors, metabolism)
• Humans
• Leukemia, Myelogenous, Chronic, BCR-ABL Positive (drug therapy)
• Mice, Transgenic
• Neoplastic Stem Cells (drug effects, pathology)
• Protein Kinase Inhibitors (pharmacology, therapeutic use)
• Proto-Oncogene Proteins c-bcl-2 (antagonists & inhibitors, metabolism)