Abstract
Cancer cells acquire disruptions in normal signal transduction pathways and homeostatic mechanisms that would trigger apoptosis in normal cells. These abnormalities include genomic instability, oncogene activation, and growth factor independent proliferation. Therefore, cancer cells likely require a block in apoptosis in order to survive. Overexpression of the antiapoptotic protein BCL-2 provides a block in apoptosis that is frequently observed in cancer cells. We have developed methods for the detection and analysis of BCL-2 dependence and here apply them to acute lymphoblastic leukemia (ALL). BH3 profiling, a mitochondrial assay that classifies blocks in the intrinsic apoptotic pathway, indicated a dependence on BCL-2 of both ALL cell lines and primary samples. This dependence predicted that BCL-2 would be complexed with select pro-death BH3 family proteins, a prediction confirmed by the isolation of BCL-2 complexes with BIM. Furthermore, the BH3 profiling and protein analysis predicted that ALL cell lines and primary cells would be sensitive to ABT-737 as a single agent. Finally, BH3 profiling and protein studies accurately predicted a relative degree of sensitivity to BCL-2 antagonism in cell lines. The ALL cells studied exhibit BCL-2 dependence, supporting clinical trials of BCL-2 antagonists in ALL as single agents or combination therapies.
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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Amino Acid Sequence
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Annexin A5 / metabolism
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Apoptosis / drug effects*
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Apoptosis Regulatory Proteins / drug effects
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Apoptosis Regulatory Proteins / physiology
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BH3 Interacting Domain Death Agonist Protein / drug effects
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BH3 Interacting Domain Death Agonist Protein / physiology
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Bcl-2-Like Protein 11
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Biphenyl Compounds / pharmacology*
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Cell Line, Tumor
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Electron Transport Complex IV / metabolism
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Humans
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Membrane Proteins / drug effects
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Membrane Proteins / physiology
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Mitochondria / enzymology
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Nitrophenols / pharmacology*
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Peptide Fragments / chemistry
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Piperazines / pharmacology
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Precursor Cell Lymphoblastic Leukemia-Lymphoma / drug therapy
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Precursor Cell Lymphoblastic Leukemia-Lymphoma / genetics*
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Precursor Cell Lymphoblastic Leukemia-Lymphoma / pathology
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Proto-Oncogene Proteins / drug effects
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Proto-Oncogene Proteins / physiology
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Proto-Oncogene Proteins c-bcl-2 / antagonists & inhibitors*
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Proto-Oncogene Proteins c-bcl-2 / physiology*
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Sulfonamides / pharmacology*
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Tumor Cells, Cultured
Substances
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ABT-737
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Annexin A5
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Apoptosis Regulatory Proteins
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BCL2L11 protein, human
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BH3 Interacting Domain Death Agonist Protein
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Bcl-2-Like Protein 11
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Biphenyl Compounds
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Membrane Proteins
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Nitrophenols
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Peptide Fragments
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Piperazines
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Proto-Oncogene Proteins
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Proto-Oncogene Proteins c-bcl-2
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Sulfonamides
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Electron Transport Complex IV