Combined targeting of BCL-2 and BCR-ABL tyrosine kinase eradicates chronic myeloid leukemia stem cells.
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.
Section of Molecular Hematology and Therapy, Department of Leukemia, University of Texas MD Anderson Cancer Center, Houston, TX 77030, USA. bicarter@mdanderson.org mandreef@mdanderson.org.
Bing Z
BZ
Carter
Section of Molecular Hematology and Therapy, Department of Leukemia, University of Texas MD Anderson Cancer Center, Houston, TX 77030, USA.
Po Yee
PY
Mak
Section of Molecular Hematology and Therapy, Department of Leukemia, University of Texas MD Anderson Cancer Center, Houston, TX 77030, USA.
Hong
H
Mu
Section of Molecular Hematology and Therapy, Department of Leukemia, University of Texas MD Anderson Cancer Center, Houston, TX 77030, USA.
Hongsheng
H
Zhou
Section of Molecular Hematology and Therapy, Department of Leukemia, University of Texas MD Anderson Cancer Center, Houston, TX 77030, USA.
Duncan H
DH
Mak
Section of Molecular Hematology and Therapy, Department of Leukemia, University of Texas MD Anderson Cancer Center, Houston, TX 77030, USA.
Wendy
W
Schober
Department of Oncology Development, AbbVie Inc., North Chicago, IL 60064, USA.
Joel D
JD
Leverson
Division of Hematopoietic Stem Cell and Leukemia Research, Beckman Research Institute, City of Hope Cancer Center, Duarte, CA 91010, USA.
Bin
B
Zhang
Division of Hematology and Oncology, University of Alabama at Birmingham, Birmingham, AL 35294, USA.
Ravi
R
Bhatia
Department of Biostatistics, University of Texas MD Anderson Cancer Center, Houston, TX 77030, USA.
Xuelin
X
Huang
Department of Leukemia, University of Texas MD Anderson Cancer Center, Houston, TX 77030, USA.
Jorge
J
Cortes
Department of Leukemia, University of Texas MD Anderson Cancer Center, Houston, TX 77030, USA.
Hagop
H
Kantarjian
Section of Molecular Hematology and Therapy, Department of Leukemia, University of Texas MD Anderson Cancer Center, Houston, TX 77030, USA.
Marina
M
Konopleva
Section of Molecular Hematology and Therapy, Department of Leukemia, University of Texas MD Anderson Cancer Center, Houston, TX 77030, USA. bicarter@mdanderson.org mandreef@mdanderson.org.
Michael
M
Andreeff
D000818:Animals; D018952:Antigens, CD34 / Q000378:metabolism; D017209:Apoptosis / Q000187:drug effects; D001752:Blast Crisis / Q000188:drug therapy / Q000473:pathology; D002453:Cell Cycle / Q000187:drug effects; D049109:Cell Proliferation / Q000187:drug effects; D016044:Fusion Proteins, bcr-abl / Q000037:antagonists & inhibitors* / Q000378:metabolism; D006801:Humans; D015464:Leukemia, Myelogenous, Chronic, BCR-ABL Positive / Q000188:drug therapy*; D008822:Mice, Transgenic; D014411:Neoplastic Stem Cells / Q000187:drug effects / Q000473:pathology*; D047428:Protein Kinase Inhibitors / Q000494:pharmacology / Q000627:therapeutic use*; D019253:Proto-Oncogene Proteins c-bcl-2 / Q000037:antagonists & inhibitors* / Q000378:metabolism
D018952:Antigens, CD34; D047428:Protein Kinase Inhibitors; D019253:Proto-Oncogene Proteins c-bcl-2; D016044:Fusion Proteins, bcr-abl