Loss of BW6 allele in the pathogenesis of malignant haematopoietic disease

Abstract

Sample from patient with myelodysplastic syndrome shows a single haplotype by sequencing typing: A∗03:01:01:01 – B∗44:10 – C∗04:01:01:01 – DRB1∗10:01:01 – DQB1∗05:01:01:01. This is an extremely rare haplotype not expected to ever appear in homozygous form. Further testing by SSP reveals a second haplotype: A∗03:01:01:01 – B∗40:02:01 – C∗02:02:02 – DRB1∗13:01:01 – DRB3∗02:02:01:01 – DQB1∗06:03:01. Sequencing depends on balanced PCR amplification of the two alleles present at a locus. SSP does not. For each PCR reaction in SSP, when both alleles are expected to be amplified, it does not matter if one or two alleles are amplified; when only one allele is expected to be amplified, there is no need for balanced amplification because only one allele is amplified. In a situation where there are two populations of cells, HLA-diploid normal cells on one hand, and HLA-haploid (with chromosome 6 deletion) malignant cells on the other hand, the first population being in minority, sequencing will only detect one haplotype, the one present in malignant cells, while SSP might detect the two haplotypes in the normal cells. In severe blast crisis not even SSP might be able to detect the deleted haplotype. It should be noted that the haplotype lost is a Bw6 haplotype, while the haplotype preserved is a Bw4 haplotype. This confirms the conclusions from previous cases where Bw6 alleles have been found to the target of HLA malignant eradication. Hypothesis: The loss of a Bw4 allele turns off T-cell cytotoxicity, but turns on NK-cell cytotoxicity still preserving cytotoxicity against malignant cells, while the loss of Bw6 allele turns off T-cell cytotoxicity without turning on NK-cell cytotoxicity eliminating immune defence against malignant cells. The possibility of HLA DNA loss or DNA mutations as a result of the malignant pathogenesis in haematopoietic malignancies must be taken into account in routine HLA typing for bone marrow transplantation. The loss of non-Bw4 HLA-A alleles and Bw6 alleles in these cases must be considered in the study of the pathogenesis of malignant haematopoietic disease.