Regulation of MHC class II expression in human T-cell malignancies.
Expression of major histocompatibility complex (MHC) class II molecules in human activated T cells is under normal circumstances regulated exclusively by the CIITA-PIII subtype of the class II transactivator (CIITA). In this study, we show that the absence of MHC class II expression in leukemic T cells was due to a lack of expression of CIITA, whereas in T-lymphoma cells, expression of CIITA correlated with expression of MHC class II. Interestingly, activation of a CIITA-promoter (P)III-reporter construct was not affected in leukemic T cells. This revealed that the absence of endogenous CIITA expression was not caused by a lack of transcription factors critical for CIITA-PIII activation but suggests the involvement of an epigenetic silencing mechanism. Subsequent analysis showed that the lack of human leukocyte antigen-DR (HLA-DR) expression correlated with hypermethylation of CIITA-PIII in leukemic T-cell lines and in primary T-cell acute lymphoblastic leukemia (T-ALL) and a T-cell prolymphocytic leukemia (T-PLL). Treatment of leukemic T-cell lines with a demethylation agent showed re-expression of CIITA-PIII and HLA-DRA. Furthermore, in vitro methylation of CIITA-PIII and subsequent assessment of CIITA-PIII activity in Jurkat leukemic T cells resulted in reduction of constitutive and CREB-1 (cyclic adenosine monophosphate [cAMP]-response element binding protein 1)-induced promoter activity. Together, these results argue for an important role of DNA hyper-methylation in the control of CIITA expression in leukemic T cells.
Holling
Tjadine M
TM
Division of Molecular Biology, Department of Immunohematology and Blood Transfusion, Leiden University Medical Center, Albinusdreef 2, 2333 ZA Leiden, The Netherlands.
Schooten
Erik
E
Langerak
Anton W
AW
van den Elsen
Peter J
PJ
D015415:Biomarkers; D004268:DNA-Binding Proteins / Q000235:genetics / Q000378:metabolism; D000949:Histocompatibility Antigens Class II / Q000235:genetics* / Q000378:metabolism; D006801:Humans; D019169:Jurkat Cells; D015463:Leukemia, Prolymphocytic / Q000378:metabolism / Q000503:physiopathology; D015458:Leukemia, T-Cell / Q000378:metabolism / Q000503:physiopathology*; D016399:Lymphoma, T-Cell / Q000378:metabolism / Q000503:physiopathology*; D008745:Methylation; D054198:Precursor Cell Lymphoblastic Leukemia-Lymphoma / Q000378:metabolism / Q000503:physiopathology; D000071701:Regulatory Factor X Transcription Factors; D014157:Transcription Factors / Q000235:genetics / Q000378:metabolism
D015415:Biomarkers; D004268:DNA-Binding Proteins; D000949:Histocompatibility Antigens Class II; D000071701:Regulatory Factor X Transcription Factors; D014157:Transcription Factors