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.
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.
Souwer
Yuri
Y
Department of Immunopathology, Sanquin Research and Landsteiner Laboratory, Academical Medical Centre, University of Amsterdam, Amsterdam, The Netherlands. y.souwer@sanquin.nl
Chamuleau
Martine E D
ME
van de Loosdrecht
Arjan A
AA
Tolosa
Eva
E
Jorritsma
Tineke
T
Muris
Jettie J F
JJ
Dinnissen-van Poppel
Marion J
MJ
Snel
Sander N
SN
van de Corput
Lisette
L
Ossenkoppele
Gert J
GJ
Meijer
Chris J L M
CJ
Neefjes
Jacques J
JJ
Marieke van Ham
S
S
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
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