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.
Publication types
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Research Support, N.I.H., Extramural
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Research Support, Non-U.S. Gov't
MeSH terms
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Apoptosis / drug effects
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Apoptosis / physiology
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Apoptosis Regulatory Proteins / genetics
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Apoptosis Regulatory Proteins / metabolism*
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Bcl-2-Like Protein 11
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Biphenyl Compounds / pharmacology
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Bortezomib / pharmacology
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Cell Line, Tumor / drug effects
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Forkhead Box Protein O3
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Forkhead Transcription Factors / genetics
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Forkhead Transcription Factors / metabolism
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Gene Expression Regulation, Neoplastic
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Humans
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Membrane Proteins / genetics
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Membrane Proteins / metabolism
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MicroRNAs / genetics
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MicroRNAs / metabolism
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Multiple Myeloma / genetics
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Multiple Myeloma / metabolism
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Multiple Myeloma / pathology
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Nitrophenols / pharmacology
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Piperazines / pharmacology
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Proto-Oncogene Proteins / genetics
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Proto-Oncogene Proteins / metabolism
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Proto-Oncogene Proteins c-bcl-2 / genetics
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Proto-Oncogene Proteins c-bcl-2 / metabolism*
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Sulfonamides / pharmacology
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Waldenstrom Macroglobulinemia / drug therapy
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Waldenstrom Macroglobulinemia / genetics
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Waldenstrom Macroglobulinemia / metabolism*
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Waldenstrom Macroglobulinemia / pathology*
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bcl-2 Homologous Antagonist-Killer Protein / genetics
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bcl-2 Homologous Antagonist-Killer Protein / metabolism
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bcl-2-Associated X Protein / genetics
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bcl-2-Associated X Protein / metabolism
Substances
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ABT-737
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Apoptosis Regulatory Proteins
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BAK1 protein, human
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BAX protein, human
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BCL2L11 protein, human
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Bcl-2-Like Protein 11
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Biphenyl Compounds
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FOXO3 protein, human
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Forkhead Box Protein O3
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Forkhead Transcription Factors
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MIRN155 microRNA, human
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Membrane Proteins
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MicroRNAs
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Nitrophenols
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Piperazines
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Proto-Oncogene Proteins
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Proto-Oncogene Proteins c-bcl-2
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Sulfonamides
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bcl-2 Homologous Antagonist-Killer Protein
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bcl-2-Associated X Protein
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Bortezomib