Low expression of pro-apoptotic Bcl-2 family proteins sets the apoptotic threshold in Waldenström macroglobulinemia

B. T. Gaudette, B. Dwivedi, K. S. Chitta, S. Poulain, D. Powell, P. Vertino, X. Leleu, S. Lonial, Asher A Chanan Khan, J. Kowalski, L. H. Boise

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Abstract

Waldenström macroglobulinemia (WM) is a proliferative disorder of IgM-secreting, lymphoplasmacytoid cells that inhabit the lymph nodes and bone marrow. The disease carries a high prevalence of activating mutations in MyD88 (91%) and CXCR4 (28%). Because signaling through these pathways leads to Bcl-xL induction, we examined Bcl-2 family expression in WM patients and cell lines. Unlike other B-lymphocyte-derived malignancies, which become dependent on expression of anti-apoptotic proteins to counter expression of pro-apoptotic proteins, WM samples expressed both pro- and anti-apoptotic Bcl-2 proteins at low levels similar to their normal B-cell and plasma cell counterparts. Three WM cell lines expressed pro-apoptotic Bcl-2 family members Bim or Bax and Bak at low levels, which determined their sensitivity to inducers of intrinsic apoptosis. In two cell lines, miR-155 upregulation, which is common in WM, was responsible for the inhibition of FOXO3a and Bim expression. Both antagonizing miR-155 to induce Bim and proteasome inhibition increased the sensitivity to ABT-737 in these lines indicating a lowering of the apoptotic threshold. In this manner, treatments that increase pro-apoptotic protein expression increase the efficacy of agents treated in combination in addition to direct killing.

Original languageEnglish (US)
Pages (from-to)479-490
Number of pages12
JournalOncogene
Volume35
Issue number4
DOIs
StatePublished - Jan 28 2016

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ASJC Scopus subject areas

  • Molecular Biology
  • Cancer Research
  • Genetics

Cite this

Gaudette, B. T., Dwivedi, B., Chitta, K. S., Poulain, S., Powell, D., Vertino, P., Leleu, X., Lonial, S., Chanan Khan, A. A., Kowalski, J., & Boise, L. H. (2016). Low expression of pro-apoptotic Bcl-2 family proteins sets the apoptotic threshold in Waldenström macroglobulinemia. Oncogene, 35(4), 479-490. https://doi.org/10.1038/onc.2015.103