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Ferrata Storti Foundation
Haematologica 2020 Volume 105(5):1274-1284
Chronic Myeloid Leukemia
Combined inhibition of MDM2 and BCR-ABL1 tyrosine kinase targets chronic myeloid leukemia stem/progenitor cells in a murine model
Bing Z. Carter,1 Po Yee Mak,1 Hong Mu,1 Xiangmeng Wang,1 Wenjing Tao,1 Duncan H. Mak,1 Elisha J. Dettman,2 Michael Cardone,2 Oleg Zernovak,3 Takahiko Seki,3 and Michael Andreeff1
1Section of Molecular Hematology and Therapy, Department of Leukemia, The University
2
of Texas MD Anderson Cancer Center, Houston, TX, USA; Eutropics, Cambridge, MA,
USA and 3Daiichi Sankyo Co. Ltd., Oncology Laboratories, R&D Division, 2-58, Hiromachi 1-Chrome, Shinagawa-ku, Tokyo, Japan
ABSTRACT
Although highly effective, BCR-ABL1 tyrosine kinase inhibitors do not target chronic myeloid leukemia (CML) stem cells. Most patients relapse upon tyrosine kinase inhibitor therapy cessation. We reported previously that combined BCR-ABL1 and BCL-2 inhibition synergistically targets CML stem/progenitor cells. p53 induces apoptosis mainly by modu- lating BCL-2 family proteins. Although infrequently mutated in CML, p53 is antagonized by MDM2, which is regulated by BCR-ABL1 signaling. We hypothesized that MDM2 inhibition could sensitize CML cells to tyrosine kinase inhibitors. Using an inducible transgenic Scl-tTa-BCR-ABL1 murine CML model, we found, by RT-PCR and CyTOF proteomics increased p53 signaling in CML bone marrow (BM) cells compared with controls in CD45+ and linage-SCA-1+C-KIT+ populations. CML BM cells were more sensitive to exogenous BH3 peptides than controls. Combined inhibition of BCR-ABL1 with imatinib and MDM2 with DS-5272 increased NOXA level, markedly reduced leukemic linage-SCA-1+C-KIT+ cells and hematopoiesis, decreased leukemia burden, significantly prolonged the survival of mice engrafted with BM cells from Scl-tTa-BCR-ABL1 mice, and significantly decreased CML stem cell frequency in secondary transplantations. Our results suggest that CML stem/progenitor cells have increased p53 signaling and a propensity for apoptosis. Combined MDM2 and BCR-ABL1 inhibition targets CML stem/progenitor cells and has the potential to improve cure rates for CML.
Introduction
Chronic myeloid leukemia (CML) originates from the t(9;22) chromosomal translo- cation that results in the BCR-ABL1 fusion gene and constitutive activation of the BCR-ABL1 tyrosine kinase in hematopoietic stem cells.1-3 CML stem cells are quies- cent,4 yet can self-renew, proliferate, differentiate, and promote expansion of the myeloid lineage. The development of imatinib and other tyrosine kinase inhibitors (TKI) has made CML, once a deadly disease, highly manageable with a 10-year overall survival rate of over 90%.
Although extremely effective in eliminating proliferating CML cells, TKI are inac- tive against quiescent CML stem cells, despite inhibition of BCR-ABL1 activity,5-7 and several clinical trials have demonstrated that approximately 50% of patients eventu- ally relapse after ceasing TKI therapy.8-11 Long-term treatment with TKI is expensive, and may lead to the development of inhibitor resistance, or intolerance to therapy. Furthermore, the persistence of CML stem cells contributes to the generation of new clones with additional acquired mutations, which can lead to progression to acute dis- ease over time. Thus, eradicating CML stem cells is the ultimate goal in curing CML.
Numerous combinatorial strategies have been proposed pre-clinically and shown to be effective in eradicating CML stem cells.12-16 Among them, concomitant targeting of
Correspondence:
BING Z. CARTER
bicarter@mdanderson.org
MICHAEL ANDREEFF
mandreef@mdanderson.org
Received: February 11, 2019. Accepted: July 26, 2019. Pre-published: August 1, 2019.
doi:10.3324/haematol.2019.219261
Check the online version for the most updated information on this article, online supplements, and information on authorship & disclosures: www.haematologica.org/content/105/5/1274
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