title: Loss of heterozygosity, a frequent but a non-exclusive mechanism responsible for HLA dysregulation in non-Hodgkin's lymphomas.
abstract: The frequent alteration of human leucocyte antigen (HLA) class I molecule expression observed in non-Hodgkin's lymphomas (NHL), similarly to solid tumours, has been reported to favour tumoral escape from the immune system. In order to identify the underlying mechanisms, we analysed 15 HLA defective NHL including partial (n = 10) and total class I (n = 5) loss, as well as HLA class II defects (n = 5). The HLA defect concerned HLA-A and -B antigens in 14 of 15 cases. In the cases with partial defect, the use of specific allelic monoclonal antibodies detected a defect of both alleles of A or B loci in six of seven tested cases. Allelic reverse transcription polymerase chain reaction (RT-PCR) demonstrated defects in six of nine cases, including four alterations of both A and B mRNA alleles. Real-time quantitative RT-PCR (RQ-PCR) did not detect the HLA-DR transcript in the two negative HLA-DR lymphomas, contrasting with the presence of CMH II transactivator (CIITA) transcript. Loss of heterozygosity (LOH) was detected in nine of 14 cases through variable pattern of nine microsatellites markers of the HLA locus. Taken together, these findings demonstrate the complexity and the variability of the mechanisms underlying HLA protein deficiencies with a high frequency of LOH. The diversity of these mechanisms indicates the importance of positive selection of HLA altered clones in the development of these NHL cases.
authors.affiliation: Laboratoire d'Hématologie-Immunologie (Pontchaillou-Chru Rennes), Laboratoire Universitaire d'Hématologie et de la biologie des cellules sanguines, Université de Rennes I, Rennes, France.
authors.forename: Bernard
authors.initials: B
authors.lastname: Drénou
authors.forename: Marcel
authors.initials: M
authors.lastname: Tilanus
authors.forename: Gilbert
authors.initials: G
authors.lastname: Semana
authors.forename: Mehdi
authors.initials: M
authors.lastname: Alizadeh
authors.forename: Brigitte
authors.initials: B
authors.lastname: Birebent
authors.forename: Jean-Marc
authors.initials: JM
authors.lastname: Grosset
authors.forename: Patricia
authors.initials: P
authors.lastname: Dias
authors.forename: Dick
authors.initials: D
authors.lastname: van Wichen
authors.forename: Yvonne
authors.initials: Y
authors.lastname: Arts
authors.forename: Dianne
authors.initials: D
authors.lastname: De Santis
authors.forename: Renée
authors.initials: R
authors.lastname: Fauchet
authors.forename: Laurence
authors.initials: L
authors.lastname: Amiot
mesh_terms: D005434:Flow Cytometry; D015870:Gene Expression; D005838:Genotype; D006680:HLA Antigens / Q000235:genetics*; D006684:HLA-DR Antigens / Q000235:genetics / Q000378:metabolism; D015395:Histocompatibility Antigens Class I / Q000235:genetics; D006801:Humans; D019656:Loss of Heterozygosity; D008228:Lymphoma, Non-Hodgkin / Q000235:genetics*; D018895:Microsatellite Repeats; D012333:RNA, Messenger / Q000235:genetics; D012334:RNA, Neoplasm / Q000235:genetics; D020133:Reverse Transcriptase Polymerase Chain Reaction; D019139:Tumor Escape / Q000235:genetics
chemical_list: D006680:HLA Antigens; D006684:HLA-DR Antigens; D015395:Histocompatibility Antigens Class I; D012333:RNA, Messenger; D012334:RNA, Neoplasm