title: Low expression of pro-apoptotic Bcl-2 family proteins sets the apoptotic threshold in Waldenström macroglobulinemia.
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.
authors.affiliation: Department of Hematology and Medical Oncology, Emory University, Atlanta, GA, USA.|Winship Cancer Institute, Emory University, Atlanta, GA, USA.|Graduate Program in Immunology and Molecular Pathogenesis, Emory University, Atlanta, GA, USA.
authors.forename: B T
authors.initials: BT
authors.lastname: Gaudette
authors.affiliation: Winship Cancer Institute, Emory University, Atlanta, GA, USA.
authors.forename: B
authors.initials: B
authors.lastname: Dwivedi
authors.affiliation: Cancer Biology, Mayo Clinic, Jacksonville, FL, USA.
authors.forename: K S
authors.initials: KS
authors.lastname: Chitta
authors.affiliation: Service d'Hématologie Immunologie Cytogénétique, Hopital de Valenciennes, Valenciennes, France.
authors.forename: S
authors.initials: S
authors.lastname: Poulain
authors.affiliation: Winship Cancer Institute, Emory University, Atlanta, GA, USA.|Department of Radiation Oncology, Emory University, Atlanta, GA, USA.
authors.forename: D
authors.initials: D
authors.lastname: Powell
authors.affiliation: Winship Cancer Institute, Emory University, Atlanta, GA, USA.|Department of Radiation Oncology, Emory University, Atlanta, GA, USA.
authors.forename: P
authors.initials: P
authors.lastname: Vertino
authors.affiliation: Service des Maladies du Sang, Hopital Claude Huriez, CHRU Lille, Lille, France.
authors.forename: X
authors.initials: X
authors.lastname: Leleu
authors.affiliation: Department of Hematology and Medical Oncology, Emory University, Atlanta, GA, USA.|Winship Cancer Institute, Emory University, Atlanta, GA, USA.
authors.forename: S
authors.initials: S
authors.lastname: Lonial
authors.affiliation: Hematology and Oncology, Mayo Clinic, Jacksonville, FL, USA.
authors.forename: A A
authors.initials: AA
authors.lastname: Chanan-Khan
authors.affiliation: Winship Cancer Institute, Emory University, Atlanta, GA, USA.
authors.forename: J
authors.initials: J
authors.lastname: Kowalski
authors.affiliation: Department of Hematology and Medical Oncology, Emory University, Atlanta, GA, USA.|Winship Cancer Institute, Emory University, Atlanta, GA, USA.|Graduate Program in Immunology and Molecular Pathogenesis, Emory University, Atlanta, GA, USA.|Department of Cell Biology, Emory University, Atlanta, GA, USA.
authors.forename: L H
authors.initials: LH
authors.lastname: Boise
mesh_terms: D017209:Apoptosis / Q000187:drug effects / Q000502:physiology; D051017:Apoptosis Regulatory Proteins / Q000235:genetics / Q000378:metabolism*; D000072224:Bcl-2-Like Protein 11; D001713:Biphenyl Compounds / Q000494:pharmacology; D000069286:Bortezomib / Q000494:pharmacology; D045744:Cell Line, Tumor / Q000187:drug effects; D000071316:Forkhead Box Protein O3; D051858:Forkhead Transcription Factors / Q000235:genetics / Q000378:metabolism; D015972:Gene Expression Regulation, Neoplastic; D006801:Humans; D008565:Membrane Proteins / Q000235:genetics / Q000378:metabolism; D035683:MicroRNAs / Q000235:genetics / Q000378:metabolism; D009101:Multiple Myeloma / Q000235:genetics / Q000378:metabolism / Q000473:pathology; D009596:Nitrophenols / Q000494:pharmacology; D010879:Piperazines / Q000494:pharmacology; D011518:Proto-Oncogene Proteins / Q000235:genetics / Q000378:metabolism; D019253:Proto-Oncogene Proteins c-bcl-2 / Q000235:genetics / Q000378:metabolism*; D013449:Sulfonamides / Q000494:pharmacology; D008258:Waldenstrom Macroglobulinemia / Q000188:drug therapy / Q000235:genetics / Q000378:metabolism* / Q000473:pathology*; D050998:bcl-2 Homologous Antagonist-Killer Protein / Q000235:genetics / Q000378:metabolism; D051028:bcl-2-Associated X Protein / Q000235:genetics / Q000378:metabolism
chemical_list: C501332:ABT-737; D051017:Apoptosis Regulatory Proteins; C494772:BAK1 protein, human; C494826:BAX protein, human; C000606775:BCL2L11 protein, human; D000072224:Bcl-2-Like Protein 11; D001713:Biphenyl Compounds; C499517:FOXO3 protein, human; D000071316:Forkhead Box Protein O3; D051858:Forkhead Transcription Factors; C524942:MIRN155 microRNA, human; D008565:Membrane Proteins; D035683:MicroRNAs; D009596:Nitrophenols; D010879:Piperazines; D011518:Proto-Oncogene Proteins; D019253:Proto-Oncogene Proteins c-bcl-2; D013449:Sulfonamides; D050998:bcl-2 Homologous Antagonist-Killer Protein; D051028:bcl-2-Associated X Protein; D000069286:Bortezomib