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 2016-01, Vol.35 (4), p.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: Article
Language:English
Subjects:
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 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
Humans
Lymphoma
Macroglobulinemia
Membrane Proteins - genetics
Membrane Proteins - metabolism
MicroRNAs - genetics
MicroRNAs - metabolism
Multiple Myeloma - genetics
Multiple Myeloma - metabolism
Multiple Myeloma - pathology
Mutation
Nitrophenols - pharmacology
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-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.
ISSN:0950-9232
1476-5594
DOI:10.1038/onc.2015.103