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Author Notes:

Corresponding author: Lawrence H. Boise, Ph.D., Winship Cancer Institute, Emory University, 1365C Clifton RD NE, Suite C4012, Atlanta GA, 30322, USA, Tel.: (404) 778-4724, Fax: (404) 778-5530, ; Email: lboise@emory.edu

We thank Stephen Ansell and Kelvin Lee for cell lines and reagents.

ABT-737 and ABT-199 were a generous gift of Abbvie (North Chicago, IL).

The authors have no relevant conflicts of interest to disclose.

Subjects:

Research Funding:

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:

  • Life Sciences & Biomedicine
  • Biochemistry & Molecular Biology
  • Oncology
  • Cell Biology
  • Genetics & Heredity
  • CELL-DEATH
  • MITOCHONDRIAL DYSFUNCTION
  • MYELOMA
  • LINE
  • BIM
  • BAX
  • ESTABLISHMENT
  • ACTIVATION
  • BCL-X(L)
  • SURVIVAL
  • Bcl-2 family
  • apoptosis
  • Waldenström Macroglobulinemia
  • miR-155

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

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Journal Title:

Oncogene

Volume:

Volume 35, Number 4

Publisher:

, Pages 479-490

Type of Work:

Article | Post-print: After Peer Review

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.

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© 2016 Macmillan Publishers Limited. All rights reserved.

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