Mechanisms of apoptosis sensitivity and resistance to the BH3 mimetic ABT-737 in acute myeloid leukemia
Marina Konopleva, Rooha Contractor, Twee Tsao, Ismael Samudio, Peter P Ruvolo, Shinichi Kitada, Xingming Deng, Dayong Zhai, Yue-Xi Shi, Thomas Sneed, Monique Verhaegen, Maria Soengas, Vivian R Ruvolo, Teresa McQueen, Wendy D Schober, Julie C Watt, Tilahun Jiffar, Xiaoyang Ling, Frank C Marini, David Harris, Martin Dietrich, Zeev Estrov, James McCubrey, W Stratford May, John C Reed, Michael Andreeff, Marina Konopleva, Rooha Contractor, Twee Tsao, Ismael Samudio, Peter P Ruvolo, Shinichi Kitada, Xingming Deng, Dayong Zhai, Yue-Xi Shi, Thomas Sneed, Monique Verhaegen, Maria Soengas, Vivian R Ruvolo, Teresa McQueen, Wendy D Schober, Julie C Watt, Tilahun Jiffar, Xiaoyang Ling, Frank C Marini, David Harris, Martin Dietrich, Zeev Estrov, James McCubrey, W Stratford May, John C Reed, Michael Andreeff
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.
Source: PubMed