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

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-...

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Bibliographic Details
Published in:	Oncogene Vol. 35; no. 4; pp. 479 - 490
Main Authors:	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
Format:	Journal Article
Language:	English
Published:	London Nature Publishing Group UK 28-01-2016 Nature Publishing Group
Subjects:	13/2 13/31 45/61 631/337/384 631/67/1990/291/1621/1915 631/80/82/23 82/80 Apoptosis Apoptosis - drug effects Apoptosis - physiology Apoptosis Regulatory Proteins - genetics Apoptosis Regulatory Proteins - metabolism Apoptotic proteins bcl-2 Homologous Antagonist-Killer Protein - genetics bcl-2 Homologous Antagonist-Killer Protein - metabolism bcl-2-Associated X Protein - genetics bcl-2-Associated X Protein - metabolism Bcl-2-Like Protein 11 Biphenyl Compounds - pharmacology Bone marrow Bortezomib - pharmacology Cell Biology Cell Line, Tumor - drug effects Cellular biology Cellular signal transduction Development and progression Forkhead Box Protein O3 Forkhead Transcription Factors - genetics Forkhead Transcription Factors - metabolism Gene expression Gene Expression Regulation, Neoplastic Genetic aspects Health aspects Human Genetics Humans Internal Medicine Lymphoma Macroglobulinemia Medicine Medicine & Public Health Membrane Proteins - genetics Membrane Proteins - metabolism MicroRNAs - genetics MicroRNAs - metabolism Multiple Myeloma - genetics Multiple Myeloma - metabolism Multiple Myeloma - pathology Mutation Nitrophenols - pharmacology Oncology original-article Piperazines - pharmacology Proteins Proto-Oncogene Proteins - genetics Proto-Oncogene Proteins - metabolism Proto-Oncogene Proteins c-bcl-2 - genetics Proto-Oncogene Proteins c-bcl-2 - metabolism Sulfonamides - pharmacology Waldenstrom Macroglobulinemia - drug therapy Waldenstrom Macroglobulinemia - genetics Waldenstrom Macroglobulinemia - metabolism Waldenstrom Macroglobulinemia - pathology
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Summary:	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-x L 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.
Bibliography:	ObjectType-Article-1 SourceType-Scholarly Journals-1 ObjectType-Feature-2 content type line 23
ISSN:	0950-9232 1476-5594
DOI:	10.1038/onc.2015.103