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, 10 (5), 375-88

Mechanisms of Apoptosis Sensitivity and Resistance to the BH3 Mimetic ABT-737 in Acute Myeloid Leukemia

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Mechanisms of Apoptosis Sensitivity and Resistance to the BH3 Mimetic ABT-737 in Acute Myeloid Leukemia

Marina Konopleva et al. Cancer Cell.

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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