Differential modulation of mutant CALR and JAK2 V617F-driven oncogenesis by HLA genotype in myeloproliferative neoplasms

It has been demonstrated previously that human leukocyte antigen class I (<i>HLA-I</i>) and class II (<i>HLA-II</i>) alleles may modulate JAK2 V617F and CALR mutation (CALRmut)-associated oncogenesis in myeloproliferative neoplasms (MPNs). However, the role of immunogenetic factors in MPNs remains underexplored. We aimed to investigate the potential involvement of <i>HLA</i> genes in CALRmut+ MPNs. High-resolution genotyping of <i>HLA-I</i> and <i>-II</i> loci was conducted in 42 CALRmut+ and 158 JAK2 V617F+ MPN patients and 1,083 healthy controls. A global analysis of the diversity of HLA-I genotypes revealed no significant differences between CALRmut+ patients and controls. However, one <i>HLA-I</i> allele (<i>C*06:02</i>) showed an inverse correlation with presence of CALR mutation. A meta-analysis across independent cohorts and healthy individuals from the 1000 Genomes Project confirmed an inverse correlation between the presentation capabilities of the <i>HLA-I</i> loci for JAK2 V617F and CALRmut-derived peptides in both patients and healthy individuals. scRNA-Seq analysis revealed low expression of <i>TAP1</i> and <i>CIITA</i> genes in CALRmut+ hematopoietic stem and progenitor cells. In conclusion, the <i>HLA-I</i> genotype differentially restricts JAK2 V617F and CALRmut-driven oncogenesis potentially explaining the mutual exclusivity of the two mutations and differences in their presentation latency. These findings have practical implications for the development of neoantigen-based vaccines in MPNs.