Department of Experimental Research, Medical University Pleven, Pleven, Bulgaria.
Department of Clinical Hematology, University Hospital Alexandrovska, Medical University, Sofia, Bulgaria.
Hum Immunol. 2023 Mar;84(3):199-207. doi: 10.1016/j.humimm.2023.01.006. Epub 2023 Jan 26.
In the present study we analyzed the relevance of HLA class II in JAK2 V617F-positive (JAK2 V617F+) myeloproliferative neoplasms (MPNs) focusing on genotype diversity, associations with specific alleles and haplotypes and the level of gene expression. One hundred and thirty-nine JAK2 V617F+ MPN patients and 1083 healthy controls, typed by Next generation sequencing (NGS) were included in the study. Multivariate generalized linear models with age as a covariate were applied for analysis of HLA-II allele and haplotype associations. Publicly available gene expression datasets were used to analyze HLA-II pathway genes expression in CD34+ stem cells (SCs) from MPN patients and healthy controls. We did not observe differences in HLA evolutionary divergence (HED) between JAK2 V617F+ MPNs and healthy controls. Two alleles: HLA-DPB103:01, DQB104:02 and 4 haplotypes: DPB102:01-DQA105:05-DQB103:01-DRB111:01, DPB104:02-DQA105:05-DQB103:01-DRB111:03, DPB102:01-DQA101:04-DQB105:03-DRB114:04, and DPB104:01-DQA103:01-DQB103:02-DRB104:01 had significantly lower frequency in MPN patients compared to controls. Additionally, we observed HLA-II alleles and haplotypes with statistically higher frequencies in JAK2 V617F+ patients. Differential gene expression analysis showed down-regulation of HLA-DRB1, -DRA, -DMA, -DMB, -DOA,-DRB4, CIITA, and CD74 genes in JAK2 V617F+ MPN CD34+ SCs as compared to normal CD34 + SCs. In conclusion, this study provides evidence for the pleiotropic effects of HLA-II genes in JAK2 V617F-driven MPNs.
在本研究中，我们分析了 HLA-II 类在 JAK2 V617F 阳性（JAK2 V617F+）骨髓增殖性肿瘤（MPN）中的相关性，重点关注基因型多样性、与特定等位基因和单倍型的关联以及基因表达水平。研究纳入了 139 名 JAK2 V617F+MPN 患者和 1083 名健康对照者，采用下一代测序（NGS）进行分型。应用包含年龄作为协变量的多变量广义线性模型分析 HLA-II 等位基因和单倍型关联。利用公共基因表达数据集分析 JAK2 V617F+MPN 患者和健康对照者 CD34+干细胞中 HLA-II 途径基因的表达。我们未观察到 JAK2 V617F+MPN 与健康对照者之间 HLA 进化分歧（HED）的差异。有两个等位基因：HLA-DPB103:01、DQB104:02 和 4 个单倍型：DPB102:01-DQA105:05-DQB103:01-DRB111:01、DPB104:02-DQA105:05-DQB103:01-DRB111:03、DPB102:01-DQA101:04-DQB105:03-DRB114:04 和 DPB104:01-DQA103:01-DQB103:02-DRB104:01 在 MPN 患者中的频率明显低于对照组。此外，我们观察到 JAK2 V617F+患者中 HLA-II 等位基因和单倍型的频率具有统计学意义上的升高。差异基因表达分析显示，与正常 CD34+SCs 相比，JAK2 V617F+MPN CD34+SCs 中 HLA-DRB1、-DRA、-DMA、-DMB、-DOA、-DRB4、CIITA 和 CD74 基因表达下调。综上所述，本研究为 HLA-II 基因在 JAK2 V617F 驱动的 MPN 中的多效性作用提供了证据。
