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.
Publication types
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Research Support, N.I.H., Extramural
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Research Support, Non-U.S. Gov't
MeSH terms
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Animals
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Apoptosis / physiology*
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Biphenyl Compounds* / metabolism
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Biphenyl Compounds* / therapeutic use
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Cell Line
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Dimerization
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Drug Resistance, Neoplasm / physiology*
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Hematopoietic Stem Cells / physiology
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Humans
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Leukemia, Myeloid, Acute* / drug therapy
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Leukemia, Myeloid, Acute* / metabolism
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Mice
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Myeloid Cell Leukemia Sequence 1 Protein
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Neoplasm Proteins / metabolism
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Nitrophenols* / metabolism
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Nitrophenols* / therapeutic use
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Piperazines / metabolism
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Piperazines / therapeutic use
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Protein Conformation
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Protein Structure, Tertiary
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Proto-Oncogene Proteins c-bcl-2 / antagonists & inhibitors*
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Proto-Oncogene Proteins c-bcl-2 / chemistry
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Proto-Oncogene Proteins c-bcl-2 / genetics
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Proto-Oncogene Proteins c-bcl-2 / metabolism
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RNA, Small Interfering / genetics
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RNA, Small Interfering / metabolism
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Recombinant Fusion Proteins / genetics
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Recombinant Fusion Proteins / metabolism
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Sulfonamides* / metabolism
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Sulfonamides* / therapeutic use
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bcl-2 Homologous Antagonist-Killer Protein / genetics
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bcl-2 Homologous Antagonist-Killer Protein / metabolism
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bcl-2-Associated X Protein / chemistry
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bcl-2-Associated X Protein / genetics
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bcl-2-Associated X Protein / metabolism
Substances
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ABT-737
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Biphenyl Compounds
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Mcl1 protein, mouse
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Myeloid Cell Leukemia Sequence 1 Protein
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Neoplasm Proteins
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Nitrophenols
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Piperazines
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Proto-Oncogene Proteins c-bcl-2
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RNA, Small Interfering
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Recombinant Fusion Proteins
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Sulfonamides
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bcl-2 Homologous Antagonist-Killer Protein
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bcl-2-Associated X Protein