Abstract
Acute myeloid leukemia (AML) frequently relapses after initial treatment. Drug resistance in AML has been attributed to high levels of the anti-apoptotic Bcl-2 family members Bcl-x(L) and Mcl-1. Here we report that removal of Mcl-1, but not loss or pharmacological blockade of Bcl-x(L), Bcl-2, or Bcl-w, caused the death of transformed AML and could cure disease in AML-afflicted mice. Enforced expression of selective inhibitors of prosurvival Bcl-2 family members revealed that Mcl-1 is critical for survival of human AML cells. Thus, targeting of Mcl-1 or regulators of its expression may be a useful strategy for the treatment of AML.
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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Antineoplastic Agents, Hormonal / pharmacology
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Apoptosis Regulatory Proteins / genetics
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Apoptosis Regulatory Proteins / metabolism
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Cell Line, Tumor
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Cell Proliferation
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Cell Survival
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Gene Deletion
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Gene Expression Regulation, Neoplastic / drug effects
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Humans
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Leukemia, Myeloid, Acute / genetics*
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Leukemia, Myeloid, Acute / pathology*
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Mice
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Mice, Inbred C57BL
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Myeloid Cell Leukemia Sequence 1 Protein
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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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Tamoxifen / pharmacology
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Tumor Cells, Cultured
Substances
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Antineoplastic Agents, Hormonal
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Apoptosis Regulatory Proteins
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Mcl1 protein, mouse
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Myeloid Cell Leukemia Sequence 1 Protein
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Proto-Oncogene Proteins c-bcl-2
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Tamoxifen