Author/Authors :
Konopleva، نويسنده , , Marina and Contractor، نويسنده , , Rooha and Tsao، نويسنده , , Twee and Samudio، نويسنده , , Ismael and Ruvolo، نويسنده , , Peter P. and Kitada، نويسنده , , Shinichi and Deng، نويسنده , , Xingming and Zhai، نويسنده , , Dayong and Shi، نويسنده , , Yue-Xi and Sneed، نويسنده , , Thomas and Verhaegen، نويسنده , , Monique and Soengas، نويسنده , , Maria and Ruvolo، نويسنده , , Vivian R. and McQueen، نويسنده , , Teresa and Schober، نويسنده , , Wendy D. and Watt، نويسنده , , Julie C. and Jiffar، نويسنده , , Tilahun and Ling، نويسنده , , Xiaoyang and Marini، نويسنده , , Frank C. and Harris، نويسنده , , David E. Dietrich، نويسنده , , Martin and Estrov، نويسنده , , Zeev and McCubrey، نويسنده , , James and May، نويسنده , , W. Stratford and Reed، نويسنده , , John C. and Andreeff، نويسنده , , Michael، نويسنده ,
Abstract :
Summary
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.
