Selective BCL-2 inhibition by ABT-199 causes on-target cell death in acute myeloid leukemia
Rongqing Pan, Leah J Hogdal, Juliana M Benito, Donna Bucci, Lina Han, Gautam Borthakur, Jorge Cortes, Daniel J DeAngelo, Lakeisha Debose, Hong Mu, Hartmut Döhner, Verena I Gaidzik, Ilene Galinsky, Leonard S Golfman, Torsten Haferlach, Karine G Harutyunyan, Jianhua Hu, Joel D Leverson, Guido Marcucci, Markus Müschen, Rachel Newman, Eugene Park, Peter P Ruvolo, Vivian Ruvolo, Jeremy Ryan, Sonja Schindela, Patrick Zweidler-McKay, Richard M Stone, Hagop Kantarjian, Michael Andreeff, Marina Konopleva, Anthony G Letai, Rongqing Pan, Leah J Hogdal, Juliana M Benito, Donna Bucci, Lina Han, Gautam Borthakur, Jorge Cortes, Daniel J DeAngelo, Lakeisha Debose, Hong Mu, Hartmut Döhner, Verena I Gaidzik, Ilene Galinsky, Leonard S Golfman, Torsten Haferlach, Karine G Harutyunyan, Jianhua Hu, Joel D Leverson, Guido Marcucci, Markus Müschen, Rachel Newman, Eugene Park, Peter P Ruvolo, Vivian Ruvolo, Jeremy Ryan, Sonja Schindela, Patrick Zweidler-McKay, Richard M Stone, Hagop Kantarjian, Michael Andreeff, Marina Konopleva, Anthony G Letai
Abstract
B-cell leukemia/lymphoma 2 (BCL-2) prevents commitment to programmed cell death at the mitochondrion. It remains a challenge to identify those tumors that are best treated by inhibition of BCL-2. Here, we demonstrate that acute myeloid leukemia (AML) cell lines, primary patient samples, and murine primary xenografts are very sensitive to treatment with the selective BCL-2 antagonist ABT-199. In primary patient cells, the median IC50 was approximately 10 nmol/L, and cell death occurred within 2 hours. Our ex vivo sensitivity results compare favorably with those observed for chronic lymphocytic leukemia, a disease for which ABT-199 has demonstrated consistent activity in clinical trials. Moreover, mitochondrial studies using BH3 profiling demonstrate activity at the mitochondrion that correlates well with cytotoxicity, supporting an on-target mitochondrial mechanism of action. Our protein and BH3 profiling studies provide promising tools that can be tested as predictive biomarkers in any clinical trial of ABT-199 in AML.
Conflict of interest statement
Conflict of Interest
A. Letai is an advisor for AbbVie and M. Konopleva has a sponsored research agreement from AbbVie. Dr. Andreeff serves on the Scientific Advisory Board of Eutropics Pharmaceuticals which once had a license for BH3 profiling.
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Source: PubMed