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  • Title: Alterations in CIITA constitute a common mechanism accounting for downregulation of MHC class II expression in diffuse large B-cell lymphoma (DLBCL).
    Author: Cycon KA, Rimsza LM, Murphy SP.
    Journal: Exp Hematol; 2009 Feb; 37(2):184-194. PubMed ID: 19081173.
    Abstract:
    OBJECTIVE: Significant decreases in patient survival are associated with downregulation of major histocompatibility complex class II (MHC-II) antigen expression in diffuse large B-cell lymphoma (DLBCL). However, the molecular mechanisms responsible for decreased MHC-II expression in DLBCL are poorly defined. We therefore examined these mechanisms in established DLBCL cell lines. MATERIALS AND METHODS: Human leukocyte antigen (HLA)-DR surface expression was examined by flow cytometry. Expression of the MHC-II genes and the MHC-II transcriptional activators class II transactivator (CIITA) and RFX was investigated by reverse transcriptase polymerase chain reaction. The integrity of the MHC-II genes was examined by polymerase chain reaction. Stable transfection assays were utilized to reconstitute CIITA expression. RESULTS: Dramatic variations in the levels of cell surface HLA-DR expression were observed on the DLBCL cell lines. OCI-Ly10 cells lack HLA-DR and HLA-DQ expression due to homozygous deletions within the MHC-II locus on chromosome 6. Dyscoordinate downregulation of MHC-II beta-chain expression in OCI-Ly3 cells mediates dramatic reductions of MHC-II surface expression. In SUDHL-4 and SUDHL-6 cells, expression of the MHC-II genes is coordinately reduced and quantitatively correlated with expression of the CIITA, the master regulator of MHC-II transcription. DB cells lack expression of CIITA and all of the MHC-II genes. Stable transfection of DB cells with CIITA expression vectors resulted in coordinate upregulation of MHC-II gene expression, which demonstrates the causal relationship between the lack of CIITA and MHC-II loss. CONCLUSIONS: These data demonstrate that downregulation of MHC-II expression occurs by multiple distinct mechanisms in DLBCL. However, decreases in CIITA expression appear to be the most prevalent mechanism.
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