Abstract 3454: Bcl-xL anti-apoptotic network is dispensable for emergence and maintenance of CML but required for disease progression, and represents an alternative target for halting survival of blast crisis CML progenitors.

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 and disease progression. 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 the development of the chronic phase-like myeloproliferative disease; however, none of the deficient mice progressed to an advanced phenotype, suggesting the importance of the anti-apoptotic Bcl-xL signaling network for the progressing early progenitor cell survival. Indeed, pharmacologic inhibition of Bcl-xL with the Bcl-xL/Bcl-2 antagonist ABT-263, combined with activation of the Bcl-xL-regulator BAD, through the PP242-mediated inhibition of mTORC1/2, markedly augmented apoptosis of BCR-ABL1+ cell lines and primary CD34+ progenitors from CML-BC but not from healthy donors, regardless of the drug-resistance effect induced by bone marrow stromal cell-generated signals. Accordingly, shRNA-mediated downregulation of BAD and the BCR-ABL1-target hnRNP A1, which promotes translation of Bcl-xL but not Bcl-2, impaired the ability of PP242 to potentiate the effect of ABT-263, and mimicked the anti-leukemic activity of ABT-263, respectively, in primary leukemic CD34+ progenitors and/or CML-BC cell lines. Thus, suppression of the antiapoptotic potential of Bcl-xL together with activation of Bad represents a novel potential pharmacologic approach for treatment of those patients undergoing blastic transformation.

Citation Format: Jason Harb, Paolo Neviani, Justin E. Ellis, Gregory J. Ferenchak, Brenda I. Chyla, Peter Hokland, Denis Claude Roy, Michael A. Caligiuri, Guido Marcucci, Claudia S. Huettner, Danilo Perrotti. Bcl-xL anti-apoptotic network is dispensable for emergence and maintenance of CML but required for disease progression, and represents an alternative target for halting survival of blast crisis CML progenitors. [abstract]. In: Proceedings of the 104th Annual Meeting of the American Association for Cancer Research; 2013 Apr 6-10; Washington, DC. Philadelphia (PA): AACR; Cancer Res 2013;73(8 Suppl):Abstract nr 3454. doi:10.1158/1538-7445.AM2013-3454