Abstract
Overexpression of the prosurvival protein Bcl-2 marks many B-lymphoid malignancies and contributes to resistance to many commonly used chemotherapeutic agents. The first effective BH3 mimetic inhibitors of Bcl-2, ABT-737 and navitoclax, also target Bcl-xL, causing dose-limiting thrombocytopenia. This prompted the development of the Bcl-2-selective antagonist, ABT-199. Here we show that in lymphoid cells, ABT-199 specifically causes Bax/Bak-mediated apoptosis that is triggered principally by the initiator BH3-only protein Bim. As expected, malignant cells isolated from patients with chronic lymphocytic leukaemia are highly sensitive to ABT-199. However, we found that normal, untransformed mature B cells are also highly sensitive to ABT-199, both in vitro and in vivo. By contrast, the B-cell precursors are largely spared, as are cells of myeloid origin. These results pinpoint the probable impact of the pharmacological inhibition of Bcl-2 by ABT-199 on the normal mature haemopoietic cell lineages in patients, and have implications for monitoring during ABT-199 therapy as well as for the clinical utility of this very promising targeted agent.
Publication types
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Comparative Study
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Research Support, Non-U.S. Gov't
MeSH terms
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Adaptor Proteins, Signal Transducing / physiology
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Animals
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Apoptosis / drug effects*
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Apoptosis Regulatory Proteins / physiology
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B-Lymphocytes / drug effects*
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B-Lymphocytes / metabolism
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Bcl-2-Like Protein 11
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Blotting, Western
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Bridged Bicyclo Compounds, Heterocyclic / pharmacology*
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Cell Proliferation / drug effects
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Drug Resistance, Neoplasm
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Flow Cytometry
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Healthy Volunteers
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Humans
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Leukemia, Lymphocytic, Chronic, B-Cell / drug therapy*
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Leukemia, Lymphocytic, Chronic, B-Cell / metabolism
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Leukemia, Lymphocytic, Chronic, B-Cell / pathology
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Membrane Proteins / physiology
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Mice
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Mice, Knockout
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Myeloid Cells / drug effects
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Myeloid Cells / metabolism
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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 / metabolism
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Proto-Oncogene Proteins c-bcl-2 / physiology
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Sulfonamides / pharmacology*
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Tumor Cells, Cultured
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Tumor Suppressor Proteins / physiology
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Xenograft Model Antitumor Assays
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bcl-2 Homologous Antagonist-Killer Protein / physiology
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bcl-2-Associated X Protein / physiology
Substances
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Adaptor Proteins, Signal Transducing
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Apoptosis Regulatory Proteins
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BCL2L11 protein, human
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Bak1 protein, mouse
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Bax protein, mouse
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Bcl-2-Like Protein 11
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Bcl2l11 protein, mouse
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Bmf protein, mouse
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Bridged Bicyclo Compounds, Heterocyclic
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Membrane Proteins
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PUMA protein, mouse
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Pmaip1 protein, mouse
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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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Tumor Suppressor Proteins
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bcl-2 Homologous Antagonist-Killer Protein
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bcl-2-Associated X Protein
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venetoclax