title: Bim polymorphisms: influence on function and response to treatment in children with acute lymphoblastic leukemia.
abstract: OBJECTIVE
  Corticosteroids induce apoptosis in the malignant lymphoid cells and are critical component of combination therapy for acute lymphoblastic leukemia (ALL). Several genome-wide microarray studies showed major implication of proapoptotic Bim in mediating corticosteroid-related resistance in leukemia cells.
  
  
  METHODS
  We investigated Bim gene polymorphisms and their association with childhood ALL outcome, and the mechanism underlying the observed finding.
  
  
  RESULTS
  Lower overall survival (OS) was associated with Bim C29201T located in Bcl-2 homology 3 (BH3) domain (P = 0.01). An association remained significant in multivariate model (P = 0.007), was more apparent in high-risk patients (P = 0.004) and patients treated with dexamethasone (P = 0.009), and was subsequently confirmed in the replication patient cohort (P = 0.03). RNA analysis revealed that C29201T affects generation of γ isoforms (γ1) that lack proapoptotic BH3 domain. The phenotypic effect was minor suggesting the influence of additional factors that may act in conjunction with Bim genotype. Combined analysis with Mcl gene polymorphism (G-486T) revealed profound reduction in OS in individuals with both risk genotypes (P < 0.0005 in discovery and P = 0.002 in replication cohort) and particularly in high-risk patients (P ≤ 0.008).
  
  
  CONCLUSIONS
  Increased expression of prosurvival Mcl1 and presence of Bim isoforms lacking proapoptotic function might explain marked reduction of OS in a disease and dose-dependent manner in ALL patients carrying Bim- and Mcl1-risk genotypes.
authors.affiliation: Authors' Affiliations: Charles Bruneau Cancer Center, Research Center CHU Sainte-Justine; Departments of Pediatrics and Pharmacology, University of Montreal; Department of Diagnostic Medicine, Jewish General Hospital, Montreal, Quebec, Canada; Departments of Pediatric Oncology and Biostatistics and Computational Biology, Dana-Farber Cancer Institute; Division of Hematology/Oncology, Children's Hospital; and Department of Pathology, Brigham and Women's Hospital, Boston, Massachusetts.
authors.forename: Vincent
authors.initials: V
authors.lastname: Gagné
authors.forename: Julie
authors.initials: J
authors.lastname: Rousseau
authors.forename: Malgorzata
authors.initials: M
authors.lastname: Labuda
authors.forename: Bahram
authors.initials: B
authors.lastname: Sharif-Askari
authors.forename: Ivan
authors.initials: I
authors.lastname: Brukner
authors.forename: Caroline
authors.initials: C
authors.lastname: Laverdière
authors.forename: Francesco
authors.initials: F
authors.lastname: Ceppi
authors.forename: Stephen E
authors.initials: SE
authors.lastname: Sallan
authors.forename: Lewis B
authors.initials: LB
authors.lastname: Silverman
authors.forename: Donna
authors.initials: D
authors.lastname: Neuberg
authors.forename: Jeffery L
authors.initials: JL
authors.lastname: Kutok
authors.forename: Daniel
authors.initials: D
authors.lastname: Sinnett
authors.forename: Maja
authors.initials: M
authors.lastname: Krajinovic
mesh_terms: D000971:Antineoplastic Combined Chemotherapy Protocols / Q000627:therapeutic use*; D017209:Apoptosis / Q000187:drug effects*; D051017:Apoptosis Regulatory Proteins / Q000235:genetics*; D000072224:Bcl-2-Like Protein 11; D015153:Blotting, Western; D049109:Cell Proliferation / Q000187:drug effects*; D002648:Child; D015331:Cohort Studies; D003907:Dexamethasone / Q000008:administration & dosage; D019008:Drug Resistance, Neoplasm; D005260:Female; D005500:Follow-Up Studies; D006801:Humans; D008297:Male; D008565:Membrane Proteins / Q000235:genetics*; D009367:Neoplasm Staging; D011110:Polymorphism, Genetic / Q000235:genetics*; D054198:Precursor Cell Lymphoblastic Leukemia-Lymphoma / Q000188:drug therapy / Q000235:genetics* / Q000401:mortality; D011241:Prednisone / Q000008:administration & dosage; D011379:Prognosis; D011518:Proto-Oncogene Proteins / Q000235:genetics*; D019253:Proto-Oncogene Proteins c-bcl-2 / Q000235:genetics; D012333:RNA, Messenger / Q000235:genetics; D060888:Real-Time Polymerase Chain Reaction; D020133:Reverse Transcriptase Polymerase Chain Reaction; D015996:Survival Rate
chemical_list: D051017:Apoptosis Regulatory Proteins; C000606775:BCL2L11 protein, human; D000072224:Bcl-2-Like Protein 11; D008565:Membrane Proteins; D011518:Proto-Oncogene Proteins; D019253:Proto-Oncogene Proteins c-bcl-2; D012333:RNA, Messenger; D003907:Dexamethasone; D011241:Prednisone
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