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

Research output: Contribution to journalArticle

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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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Waldenstrom Macroglobulinemia
Apoptosis Regulatory Proteins
Proteins
Cell Line
B-Lymphocytes
Proteasome Endopeptidase Complex
Plasma Cells
Immunoglobulin M
Up-Regulation
Lymph Nodes
Bone Marrow
Apoptosis
Mutation
Neoplasms

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., ... 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

Low expression of pro-apoptotic Bcl-2 family proteins sets the apoptotic threshold in Waldenström macroglobulinemia. / Gaudette, B. T.; Dwivedi, B.; Chitta, K. S.; Poulain, S.; Powell, D.; Vertino, P.; Leleu, X.; Lonial, S.; Chanan Khan, Asher A; Kowalski, J.; Boise, L. H.

In: Oncogene, Vol. 35, No. 4, 28.01.2016, p. 479-490.

Research output: Contribution to journalArticle

Gaudette, BT, Dwivedi, B, Chitta, KS, Poulain, S, Powell, D, Vertino, P, Leleu, X, Lonial, S, Chanan Khan, AA, Kowalski, J & Boise, LH 2016, 'Low expression of pro-apoptotic Bcl-2 family proteins sets the apoptotic threshold in Waldenström macroglobulinemia', Oncogene, vol. 35, no. 4, pp. 479-490. https://doi.org/10.1038/onc.2015.103
Gaudette, B. T. ; Dwivedi, B. ; Chitta, K. S. ; Poulain, S. ; Powell, D. ; Vertino, P. ; Leleu, X. ; Lonial, S. ; Chanan Khan, Asher A ; Kowalski, J. ; Boise, L. H. / Low expression of pro-apoptotic Bcl-2 family proteins sets the apoptotic threshold in Waldenström macroglobulinemia. In: Oncogene. 2016 ; Vol. 35, No. 4. pp. 479-490.
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