title: Detection of aberrant transcription of major histocompatibility complex class II antigen presentation genes in chronic lymphocytic leukaemia identifies HLA-DOA mRNA as a prognostic factor for survival.
abstract: In human B cells, effective major histocompatibility complex (MHC) class II-antigen presentation depends not only on MHC class II, but also on the invariant chain (CD74 or Ii), HLA-DM (DM) and HLA-DO (DO), the chaperones regulating the antigen loading process of MHC class II molecules. We analysed immediate ex vivo expression of HLA-DR (DR), CD74, DM and DO in B cell chronic lymphocytic leukaemia (B-CLL). Real-time reverse transcription polymerase chain reaction demonstrated a highly significant upregulation of DRA, CD74, DMB, DOA and DOB mRNA in purified malignant cells compared to B cells from healthy donors. The increased mRNA levels were not translated into enhanced protein levels but could reflect aberrant transcriptional regulation. Indeed, upregulation of DRA, DMB, DOA and DOB mRNA correlated with enhanced expression of class II transactivator (CIITA). In-depth analysis of the various CIITA transcripts demonstrated a significant increased activity of the interferon-gamma-inducible promoter CIITA-PIV in B-CLL. Comparison of the aberrant mRNA levels with clinical outcome identified DOA mRNA as a prognostic indicator for survival. Multivariate analysis revealed that the prognostic value of DOA mRNA was independent of the mutational status of the IGHV genes. Thus, aberrant transcription of DOA forms a novel and additional prognostic indicator for survival in B-CLL.
authors.affiliation: Department of Immunopathology, Sanquin Research and Landsteiner Laboratory, Academical Medical Centre, University of Amsterdam, Amsterdam, The Netherlands. y.souwer@sanquin.nl
authors.forename: Yuri
authors.initials: Y
authors.lastname: Souwer
authors.forename: Martine E D
authors.initials: ME
authors.lastname: Chamuleau
authors.forename: Arjan A
authors.initials: AA
authors.lastname: van de Loosdrecht
authors.forename: Eva
authors.initials: E
authors.lastname: Tolosa
authors.forename: Tineke
authors.initials: T
authors.lastname: Jorritsma
authors.forename: Jettie J F
authors.initials: JJ
authors.lastname: Muris
authors.forename: Marion J
authors.initials: MJ
authors.lastname: Dinnissen-van Poppel
authors.forename: Sander N
authors.initials: SN
authors.lastname: Snel
authors.forename: Lisette
authors.initials: L
authors.lastname: van de Corput
authors.forename: Gert J
authors.initials: GJ
authors.lastname: Ossenkoppele
authors.forename: Chris J L M
authors.initials: CJ
authors.lastname: Meijer
authors.forename: Jacques J
authors.initials: JJ
authors.lastname: Neefjes
authors.forename: S
authors.initials: S
authors.lastname: Marieke van Ham
mesh_terms: D000368:Aged; D017951:Antigen Presentation / Q000235:genetics; D000944:Antigens, Differentiation, B-Lymphocyte / Q000235:genetics; D016022:Case-Control Studies; D004591:Electrophoresis, Polyacrylamide Gel / Q000379:methods; D005260:Female; D015972:Gene Expression Regulation, Neoplastic; D006681:HLA-D Antigens / Q000235:genetics*; D006684:HLA-DR Antigens / Q000235:genetics; D000949:Histocompatibility Antigens Class II / Q000235:genetics; D006801:Humans; D015451:Leukemia, Lymphocytic, Chronic, B-Cell / Q000235:genetics*; D008297:Male; D008875:Middle Aged; D009687:Nuclear Proteins / Q000235:genetics*; D011379:Prognosis; D011401:Promoter Regions, Genetic; D016016:Proportional Hazards Models; D012333:RNA, Messenger / Q000032:analysis*; D020133:Reverse Transcriptase Polymerase Chain Reaction / Q000379:methods; D015534:Trans-Activators / Q000235:genetics*; D014158:Transcription, Genetic
chemical_list: D000944:Antigens, Differentiation, B-Lymphocyte; D006681:HLA-D Antigens; C084245:HLA-DM antigens; C046148:HLA-DO antigens; D006684:HLA-DR Antigens; D000949:Histocompatibility Antigens Class II; C083728:MHC class II transactivator protein; D009687:Nuclear Proteins; D012333:RNA, Messenger; D015534:Trans-Activators; C045084:invariant chain