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

Leukemia. 2014 Jun;28(6):1207-15. doi: 10.1038/leu.2014.1. Epub 2014 Jan 9.


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

  • Comparative Study
  • Research Support, Non-U.S. Gov't

MeSH terms

  • Adaptor Proteins, Signal Transducing / physiology
  • Animals
  • Apoptosis / drug effects*
  • Apoptosis Regulatory Proteins / physiology
  • B-Lymphocytes / drug effects*
  • B-Lymphocytes / metabolism
  • Bcl-2-Like Protein 11
  • Blotting, Western
  • Bridged Bicyclo Compounds, Heterocyclic / pharmacology*
  • Cell Proliferation / drug effects
  • Drug Resistance, Neoplasm
  • Flow Cytometry
  • Healthy Volunteers
  • Humans
  • Leukemia, Lymphocytic, Chronic, B-Cell / drug therapy*
  • Leukemia, Lymphocytic, Chronic, B-Cell / metabolism
  • Leukemia, Lymphocytic, Chronic, B-Cell / pathology
  • Membrane Proteins / physiology
  • Mice
  • Mice, Knockout
  • Myeloid Cells / drug effects
  • Myeloid Cells / metabolism
  • Proto-Oncogene Proteins / physiology
  • Proto-Oncogene Proteins c-bcl-2 / antagonists & inhibitors*
  • Proto-Oncogene Proteins c-bcl-2 / metabolism
  • Proto-Oncogene Proteins c-bcl-2 / physiology
  • Sulfonamides / pharmacology*
  • Tumor Cells, Cultured
  • Tumor Suppressor Proteins / physiology
  • Xenograft Model Antitumor Assays
  • bcl-2 Homologous Antagonist-Killer Protein / physiology
  • bcl-2-Associated X Protein / physiology


  • Adaptor Proteins, Signal Transducing
  • Apoptosis Regulatory Proteins
  • BCL2L11 protein, human
  • Bak1 protein, mouse
  • Bax protein, mouse
  • Bcl-2-Like Protein 11
  • Bcl2l11 protein, mouse
  • Bmf protein, mouse
  • Bridged Bicyclo Compounds, Heterocyclic
  • Membrane Proteins
  • PUMA protein, mouse
  • Pmaip1 protein, mouse
  • Proto-Oncogene Proteins
  • Proto-Oncogene Proteins c-bcl-2
  • Sulfonamides
  • Tumor Suppressor Proteins
  • bcl-2 Homologous Antagonist-Killer Protein
  • bcl-2-Associated X Protein
  • venetoclax