Both leukaemic and normal peripheral B lymphoid cells are highly sensitive to the selective pharmacological inhibition of prosurvival Bcl-2 with ABT-199

Autor: Philippe Bouillet, Stefan P Glaser, Seong Lin Khaw, Delphine Merino, David C.S. Huang, Andrew W. Roberts, Mary Ann Anderson
Rok vydání: 2013
Předmět:
Cancer Research
Myeloid
Chronic lymphocytic leukemia
Blotting
Western
Apoptosis
chemistry.chemical_compound
Mice
Bcl-2-associated X protein
Proto-Oncogene Proteins
medicine
Tumor Cells
Cultured
Animals
Humans
Myeloid Cells
B cell
Adaptor Proteins
Signal Transducing
Cell Proliferation
bcl-2-Associated X Protein
Mice
Knockout
B-Lymphocytes
Sulfonamides
Navitoclax
biology
Bcl-2-Like Protein 11
Cell growth
Tumor Suppressor Proteins
Membrane Proteins
Hematology
medicine.disease
Bridged Bicyclo Compounds
Heterocyclic
Flow Cytometry
Leukemia
Lymphocytic
Chronic
B-Cell
Xenograft Model Antitumor Assays
Healthy Volunteers
Leukemia
medicine.anatomical_structure
bcl-2 Homologous Antagonist-Killer Protein
Oncology
chemistry
Proto-Oncogene Proteins c-bcl-2
Drug Resistance
Neoplasm
Immunology
biology.protein
Cancer research
Apoptosis Regulatory Proteins
Bcl-2 Homologous Antagonist-Killer Protein
Zdroj: Leukemia. 28(6)
ISSN: 1476-5551
Popis: 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.
Databáze: OpenAIRE
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