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|Ref Type||Journal Article|
|Authors||Chang CC, Ogino T, Mullins DW, Oliver JL, Yamshchikov GV, Bandoh N, Slingluff CL Jr, Ferrone S|
|Title||Defective human leukocyte antigen class I-associated antigen presentation caused by a novel beta2-microglobulin loss-of-function in melanoma cells.|
|Journal||The Journal of biological chemistry|
|Date||2006 Jul 7|
|Abstract Text||The major histocompatibility complex class I molecules consist of three subunits, the 45-kDa heavy chain, the 12-kDa beta(2)-microglobulin (beta(2)m), and an approximately 8-9-residue antigenic peptide. Without beta(2)m, the major histocompatibility complex class I molecules cannot assemble, thereby abolishing their transport to the cell membrane and the subsequent recognition by antigen-specific T cells. Here we report a case of defective antigen presentation caused by the expression of a beta(2)m with a Cys-to-Trp substitution at position 25 (beta(2)m(C25W)). This substitution causes misfolding and degradation of beta(2)m(C25W) but does not result in complete lack of human leukocyte antigen (HLA) class I molecule expression on the surface of melanoma VMM5B cells. Despite HLA class I expression, VMM5B cells are not recognized by HLA class I-restricted, melanoma antigen-specific cytotoxic T lymphocytes even following loading with exogenous peptides or transduction with melanoma antigen-expressing viruses. Lysis of VMM5B cells is restored only following reconstitution with exogenous or endogenous wild-type beta(2)m protein. Together, our results indicate impairment of antigenic peptide presentation because of a dysfunctional beta(2)m and provide a mechanism for the lack of close association between HLA class I expression and susceptibility of tumor cells to cytotoxic T lymphocytes-mediated lysis in malignant diseases.|
|Molecular Profile||Treatment Approach|
|Gene Name||Source||Synonyms||Protein Domains||Gene Description||Gene Role|
|Therapy Name||Drugs||Efficacy Evidence||Clinical Trials|
|Drug Name||Trade Name||Synonyms||Drug Classes||Drug Description|
|Gene||Variant||Impact||Protein Effect||Variant Description||Associated with drug Resistance|
|B2M||C45W||missense||loss of function - predicted||B2M C45W lies within the Ig-like C1-type domain of the B2m protein (UniProt.org). C45W results in the loss of the disulfide bond between C45 and C100 (PMID: 16648140), increased degradation of B2m, down regulation of HLA class I molecules, and defects in antigen presentation in cultured cells (PMID: 16648140), and therefore, is predicted to result in a loss of B2m protein function.|
|Molecular Profile||Indication/Tumor Type||Response Type||Therapy Name||Approval Status||Evidence Type||Efficacy Evidence||References|
|B2M C45W||melanoma||resistant||Interferon gamma||Preclinical - Cell culture||Actionable||In a preclinical study, a melanoma cell line harboring B2M C45W displayed greatly reduced expression of HLA class I molecules, which was not corrected by treatment with interferon gamma (PMID: 16648140).||16648140|