Title |
Selective BCL-2 Inhibition by ABT-199 Causes On-Target Cell Death in Acute Myeloid Leukemia
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Published in |
Cancer Discovery, March 2014
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DOI | 10.1158/2159-8290.cd-13-0609 |
Pubmed ID | |
Authors |
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. |
X Demographics
Geographical breakdown
Country | Count | As % |
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United States | 5 | 45% |
Singapore | 1 | 9% |
Unknown | 5 | 45% |
Demographic breakdown
Type | Count | As % |
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Members of the public | 9 | 82% |
Science communicators (journalists, bloggers, editors) | 1 | 9% |
Scientists | 1 | 9% |
Mendeley readers
Geographical breakdown
Country | Count | As % |
---|---|---|
United Kingdom | 2 | <1% |
Germany | 1 | <1% |
Australia | 1 | <1% |
India | 1 | <1% |
Canada | 1 | <1% |
Spain | 1 | <1% |
United States | 1 | <1% |
Unknown | 362 | 98% |
Demographic breakdown
Readers by professional status | Count | As % |
---|---|---|
Researcher | 72 | 19% |
Student > Ph. D. Student | 60 | 16% |
Student > Bachelor | 31 | 8% |
Student > Master | 28 | 8% |
Student > Doctoral Student | 19 | 5% |
Other | 60 | 16% |
Unknown | 100 | 27% |
Readers by discipline | Count | As % |
---|---|---|
Biochemistry, Genetics and Molecular Biology | 84 | 23% |
Medicine and Dentistry | 81 | 22% |
Agricultural and Biological Sciences | 53 | 14% |
Pharmacology, Toxicology and Pharmaceutical Science | 19 | 5% |
Immunology and Microbiology | 8 | 2% |
Other | 18 | 5% |
Unknown | 107 | 29% |