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

• Type of Material: Article
• Authors: Brian T. Gaudette, Emory University; Bhakti Dwivedi, Emory University; Kasyapa Chitta, Mayo Clinic; Stéphanie Poulain, Hopital de Valenciennes; Doris Powell, Emory University; Paula Vertino, Emory University; Xavier Leleu, CHRU Lille; Sagar Lonial, Emory University; Asher A. Chanan-Khan, Mayo Clinic; Jeanne Kowalski, Emory University; Lawrence Boise, Emory University
• Language: English
• Date: 2016-01-28
• Publisher: Nature Publishing Group
• Publication Version: Author Accepted Manuscript (After Peer Review)
• Copyright Statement: © 2016 Macmillan Publishers Limited. All rights reserved.
• Final Published Version (URL): http://dx.doi.org/10.1038/onc.2015.103
• Title of Journal or Parent Work: Oncogene
• ISSN: 0950-9232
• Volume: 35
• Issue: 4
• Start Page: 479
• End Page: 490
• Grant/Funding Information: This work was supported by R01 CA127910 and R01 CA129968 as well as funding from the TJ Martell Foundation (LHB), the Leukemia & Lymphoma Society (AAC), the International Waldenstrom Macroglobulinemia (AAC) and the Comité du Septentrion de la Ligue contre le Cancer (XL). LHB is a GRA Distinguished Cancer Scientist.
• Keywords: BCL-X(L); MITOCHONDRIAL DYSFUNCTION; apoptosis; Life Sciences & Biomedicine; ESTABLISHMENT; miR-155; Bcl-2 family; Genetics & Heredity; LINE; Biochemistry & Molecular Biology; MYELOMA; BAX; Waldenström Macroglobulinemia; BIM; SURVIVAL; ACTIVATION; Cell Biology; CELL-DEATH; Oncology
• Research Categories: Health Sciences, Oncology; Biology, Cell

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.