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Mechanisms of apoptosis sensitivity and resistance to the BH3 mimetic ABT-737 in acute myeloid leukemia |
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| Authors: | Konopleva Marina Contractor Rooha Tsao Twee Samudio Ismael Ruvolo Peter P Kitada Shinichi Deng Xingming Zhai Dayong Shi Yue-Xi Sneed Thomas Verhaegen Monique Soengas Maria Ruvolo Vivian R McQueen Teresa Schober Wendy D Watt Julie C Jiffar Tilahun Ling Xiaoyang Marini Frank C Harris David Dietrich Martin Estrov Zeev McCubrey James May W Stratford Reed John C Andreeff Michael |
| Affiliation: | Section of Molecular Hematology and Therapy, Department of Blood and Marrow Transplantation, The University of Texas M D Anderson Cancer Center, Houston, Texas 77030, USA. |
| Abstract: | BCL-2 proteins are critical for cell survival and are overexpressed in many tumors. ABT-737 is a small-molecule BH3 mimetic that exhibits single-agent activity against lymphoma and small-cell lung cancer in preclinical studies. We here report that ABT-737 effectively kills acute myeloid leukemia blast, progenitor, and stem cells without affecting normal hematopoietic cells. ABT-737 induced the disruption of the BCL-2/BAX complex and BAK-dependent but BIM-independent activation of the intrinsic apoptotic pathway. In cells with phosphorylated BCL-2 or increased MCL-1, ABT-737 was inactive. Inhibition of BCL-2 phosphorylation and reduction of MCL-1 expression restored sensitivity to ABT-737. These data suggest that ABT-737 could be a highly effective antileukemia agent when the mechanisms of resistance identified here are considered. |
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