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ORIGINAL RESEARCH article

Front. Immunol.
Sec. Cancer Immunity and Immunotherapy
Volume 15 - 2024 | doi: 10.3389/fimmu.2024.1427810

Differential Modulation of Mutant CALR and JAK2 V617F-Driven Oncogenesis by HLA Genotype in Myeloproliferative Neoplasms

Provisionally accepted
Velizar S. Shivarov Velizar S. Shivarov 1*Gergana Tsvetkova Gergana Tsvetkova 2Ilina Micheva Ilina Micheva 3Evgueniy Hadjiev Evgueniy Hadjiev 2Jasmina Petrova Jasmina Petrova 4Anela Ivanova Anela Ivanova 4Galia Madjarova Galia Madjarova 4Milena I. Ivanova - Shivarova Milena I. Ivanova - Shivarova 5*
  • 1 Other, Pleven, Bulgaria
  • 2 Other, Sofia, Bulgaria
  • 3 Other, Varna, Bulgaria
  • 4 Department of Physical Chemistry, Faculty of Chemistry and Pharmacy, Sofia University, Sofia, Bulgaria
  • 5 Department of Clinical Immunology with Stem Cell Bank, Aleksandrovska University Hospital, Sofia, Bulgaria

The final, formatted version of the article will be published soon.

    It has been demonstrated previously that Human Leukocyte Antigen class I (HLA-I) and class II (HLA-II) 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 HLA genes in CALRmut+ MPNs. High-resolution genotyping of HLA-I and -II loci was conducted in 42 CALRmut+ and 158 JAK2 V617F+ MPN patients, and 1083 healthy controls. A global analysis of the diversity of HLA-I genotypes revealed no significant differences between CALRmut+ patients and controls. However, one HLA-I allele (C*06:02) 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 presentation capabilities of the HLA-I loci for JAK2 V617F and CALRmut-derived peptides in both patients and healthy individuals. scRNA-Seq analysis revealed low expression of TAP1 and CIITA genes in CALRmut+ hematopoietic stem and progenitor cells. In conclusion, the HLA-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.

    Keywords: Immunoediting, HLA, MPN, Mutation, CALR, JAK2 V617F, neoantigen

    Received: 08 May 2024; Accepted: 26 Aug 2024.

    Copyright: © 2024 Shivarov, Tsvetkova, Micheva, Hadjiev, Petrova, Ivanova, Madjarova and Ivanova - Shivarova. This is an open-access article distributed under the terms of the Creative Commons Attribution License (CC BY). The use, distribution or reproduction in other forums is permitted, provided the original author(s) or licensor are credited and that the original publication in this journal is cited, in accordance with accepted academic practice. No use, distribution or reproduction is permitted which does not comply with these terms.

    * Correspondence:
    Velizar S. Shivarov, Other, Pleven, Bulgaria
    Milena I. Ivanova - Shivarova, Department of Clinical Immunology with Stem Cell Bank, Aleksandrovska University Hospital, Sofia, Bulgaria

    Disclaimer: All claims expressed in this article are solely those of the authors and do not necessarily represent those of their affiliated organizations, or those of the publisher, the editors and the reviewers. Any product that may be evaluated in this article or claim that may be made by its manufacturer is not guaranteed or endorsed by the publisher.