Altered binding of regulatory factors to HLA class I enhancer sequence in human tumor cell lines lacking class I antigen expression.

Blanchet, Odile; Bourge, Jean‐François; Zinszner, Hélène; Israël, Alain; Kourilsky, Philippe; Dausset, J; Degos, Laurent; Paul, Pascale

doi:10.1073/pnas.89.8.3488

Cited by 59 publications

(27 citation statements)

References 26 publications

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“…6 Besides these irreversible defects, different molecular mechanisms of reversible transcriptional downregulation of HLA class I antigen expression have been described, including silencing of HLA class I gene transcription by hypermethylation of the corresponding promoters and altered binding of regulatory factors to the HLA class I heavy chain enhancer element. 7,26 Total lack of HLA class I antigen presentation enables the tumor to escape immune recognition by CTLs, which might explain the marked clinical evolution of patient UKRV-Mel-2. All tumor samples analyzed in our study, the tissue cells from an early lymph node metastasis as well as the cells from both tumor lines, exhibited an HLA class I-negative phenotype, though the samples were taken at different time points from different locations.…”

Section: Discussionmentioning

confidence: 99%

Complete loss of HLA class I antigen expression on melanoma cells: A result of successive mutational events

Paschen

Méndez

Jiménez

et al. 2002

Intl Journal of Cancer

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Alterations in the surface expression of HLA class I molecules have been described as a strategy of tumors to evade recognition by cytotoxic T cells. We detected complete loss of HLA class I antigen presentation for 2 tumor cell lines from 1 melanoma patient, the first originated from a regional lymph node lesion diagnosed simultaneously with the primary tumor and the second established 8 months later from a metastatic pleural effusion sample. Antigen presentation was not inducible with IFN-␥ but could be restored after transfection of tumor cells with b2m cDNA, indicating a defect in b2m expression. Analysis of the nature of this defect revealed that it originated from at least 2 mutational events affecting both copies of the b2m gene: a microdeletion of 498 bp in one b2m gene, including its entire exon 1, and a macrodeletion involving the entire copy of the second b2m gene. Microsatellite analysis pointed to the macrodeletion by demonstrating LOH for several specific markers on the long arm (q) of chromosome 15. Structural imbalance of 15q was verified by FISH. FISH studies also indicated the coexistence of a structurally abnormal variant of chromosome 15q with 2 apparently entire chromosomes 15q harboring the homozygous b2m microdeletion. Block of b2m expression in tumor cells builds a barrier to immunotherapy of cancer patients, and its early incidence should be of major consideration in the development and design of immunotherapeutic strategies.

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Section: Discussionmentioning

confidence: 99%

Complete loss of HLA class I antigen expression on melanoma cells: A result of successive mutational events

Paschen

Méndez

Jiménez

et al. 2002

Intl Journal of Cancer

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“…Some of these genes, such as those encoding class I heavy chains, ␤ 2 m, and TAP1, are partially suppressed, whereas transcripts encoded by TAP2, LMP2, and LMP7 genes are undetectable, as are the corresponding protein products. In other tumors, other combinations of these genes are down-regulated (24,29,46,47).…”

Section: Discussionmentioning

confidence: 99%

Organization and Functional Analysis of the Mouse Transporter Associated with Antigen Processing 2 Promoter

Arons

Kunin

Schechter

et al. 2001

The Journal of Immunology

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In accordance with the key role of MHC class I molecules in the adaptive immune response against viruses, they are expressed by most cells, and their expression can be enhanced by cytokines. The assembly and cell surface expression of class I complexes depend on a continuous peptide supply. The peptides are generated mainly by the proteasome and are transported to the endoplasmic reticulum by a peptide transport pump consisting of two subunits, TAP1 and TAP2. The proteasome low molecular weight polypeptide (2 and 7), as well as TAP (1 and 2) genes, are coordinately regulated and are induced by IFNs. Despite this coordinate regulation, examination of tumors shows that these genes can be discordantly down-regulated. In pursuing a molecular explanation for these observations, we have characterized the mouse TAP2 promoter region and 5′-flanking sequence. We show that the 5′ untranslated regions of TAP2 genes have a characteristic genomic organization that is conserved in both the mouse and the human. The mouse TAP2 promoter belongs to a class of promoters that lack TATA boxes but contain a MED1 (multiple start site element downstream) sequence. Accordingly, transcription is initiated from multiple sites within a 100-nucleotide window. An IFN regulatory factor 1 (IRF1)/IRF2 binding site is located in this region and is involved in both basal and IRF1-induced TAP2 promoter activity. The implication of the extensive differences found among the promoters of class I heavy chain, low molecular weight polypeptide, and TAP genes, all encoding proteins involved in Ag presentation, is discussed.

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“…Nuclear localization of p65 and relB has been previously shown to correlate with DC maturation and efficient antigen presentation (29)(30)(31). The profound induction of both branches of NF-B activation by NIK results in the up-regulation of several antigenpresenting and costimulatory molecules, cytokines, and chemokines that contain NF-B sites in the promoters of their genes (32)(33)(34)(35)(36)(37). Interestingly, IL-1␤ and IP-10 that also contain NF-B sites in their promoters were not induced by NIK.…”

Section: Discussionmentioning

confidence: 99%

Activation of NF-κB by the intracellular expression of NF-κB-inducing kinase acts as a powerful vaccine adjuvant

Andreakos

Williams

Wales

et al. 2006

Proc. Natl. Acad. Sci. U.S.A.

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Altered binding of regulatory factors to HLA class I enhancer sequence in human tumor cell lines lacking class I antigen expression.

Cited by 59 publications

References 26 publications

Complete loss of HLA class I antigen expression on melanoma cells: A result of successive mutational events

Complete loss of HLA class I antigen expression on melanoma cells: A result of successive mutational events

Organization and Functional Analysis of the Mouse Transporter Associated with Antigen Processing 2 Promoter

Activation of NF-κB by the intracellular expression of NF-κB-inducing kinase acts as a powerful vaccine adjuvant

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