Mechanisms of apoptosis sensitivity and resistance to the BH3 mimetic ABT-737 in acute myeloid leukemia

  • Cancer Cell. 2006 Nov;10(5):375-88. doi: 10.1016/j.ccr.2006.10.006.
Marina Konopleva  1 ,  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
Affiliations
  • 1. 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.
PMID: 17097560 DOI: 10.1016/j.ccr.2006.10.006
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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