Abstract
The dismal outcome of blast crisis chronic myelogenous leukemia (CML-BC) patients underscores the need for a better understanding of the mechanisms responsible for the development of drug resistance. Altered expression of the anti-apoptoticBcl-xL has been correlated with BCR-ABL leukemogenesis; however, its involvement in the pathogenesis and evolution of CML has not been formally demonstrated yet. Thus, we generated an inducible mouse model in which simultaneous expression of p210-BCR-ABL1 and deletion of bcl-x occurs within hematopoietic stem and progenitor cells. Absence of Bcl-xL did not affect development of the chronic phase-like myeloproliferative disease, but none of the deficient mice progressed to an advanced phenotype, suggesting the importance of Bcl-xL in survival of progressing early progenitor cells. Indeed, pharmacological antagonism of Bcl-xL, with ABT-263, combined with PP242-induced activation of BAD markedly augmented apoptosis of CML-BC cell lines and primary CD34+ progenitors but not those from healthy donors, regardless of drug resistance induced by bone marrow stromal cell-generated signals. Moreover, studies in which BAD or Bcl-xL expression was molecularly altered strongly support their involvement in ABT-263/PP242-induced apoptosis of CML-BC progenitors. Thus, suppression of the antiapoptotic potential of Bcl-xL together with BAD activation represents an effective pharmacological approach for patients undergoing blastic transformation.
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Acknowledgements
DP is a Scholar of The Leukemia and Lymphoma Society. This work was supported, in part, by NIH Grants CA095512 and CA163800 (DP), CA16058 (OSU-CCC); Fonds de Recherche Quebec Sante—TheCell (DCR); Lauri Strauss Leukemia and BloodCenter Research Foundations (CSH); the Danish Medical Research Council, the Danish Cancer Society and the Karen Elise Jensen Foundation (PH) grants. JGH was supported, in part, by NIH training Grant HL-07209. We thank L. Hennighausen (NIH, Bethesda, MD, USA) for providing Bcl-x f/f mice; H. Albertz and C. Reinbold (FACS Core Facility, Blood Research Institute, Milwaukee, WI, USA) for technical assistance; J. Perrin (OSU Medical Center, Columbus, OH, USA) for helping in procuring CML specimens andS. Lee (OSU Medical Center, Columbus, OH, USA) for editorial assistance.
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JGH designed, performed experiments and drafted the manuscript; PN, BJC, JJE, CJW, JJO and GJF performed the experiments; GM, PH and DCR provided the patient specimens; MAC and GM provided vital instrumentation and reagents; CSH designed the mouse study; and DP supervised the work and wrote the manuscript. All authors contributed to and approved the final manuscript.
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Harb, J., Neviani, P., Chyla, B. et al. Bcl-xL anti-apoptotic network is dispensable for development and maintenance of CML but is required for disease progression where it represents a new therapeutic target. Leukemia 27, 1996–2005 (2013). https://doi.org/10.1038/leu.2013.151
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DOI: https://doi.org/10.1038/leu.2013.151
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