Loss of heterozygosity, a frequent but a non-exclusive mechanism responsible for HLA dysregulation in non-Hodgkin's lymphomas.
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.
Drénou
Bernard
B
Laboratoire d'Hématologie-Immunologie (Pontchaillou-Chru Rennes), Laboratoire Universitaire d'Hématologie et de la biologie des cellules sanguines, Université de Rennes I, Rennes, France.
Tilanus
Marcel
M
Semana
Gilbert
G
Alizadeh
Mehdi
M
Birebent
Brigitte
B
Grosset
Jean-Marc
JM
Dias
Patricia
P
van Wichen
Dick
D
Arts
Yvonne
Y
De Santis
Dianne
D
Fauchet
Renée
R
Amiot
Laurence
L
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
D006680:HLA Antigens; D006684:HLA-DR Antigens; D015395:Histocompatibility Antigens Class I; D012333:RNA, Messenger; D012334:RNA, Neoplasm