PMID- 33017633
OWN - NLM
STAT- MEDLINE
DCOM- 20210114
LR  - 20210114
IS  - 1873-2399 (Electronic)
IS  - 0301-472X (Linking)
VI  - 92
DP  - 2020 Dec
TI  - Probable HLA-mediated immunoediting of JAK2 V617F-driven oncogenesis.
PG  - 75-88.e10
LID - S0301-472X(20)30565-8 [pii]
LID - 10.1016/j.exphem.2020.09.200 [doi]
AB  - Human leukocyte antigen class I (HLA-I) genotype has been found to influence 
      cancer development through the presentation of mutational neoepitopes. However, 
      our understanding of its effect on the development of myeloproliferative 
      neoplasms (MPNs) remains limited. We aimed to elucidate the putative protective 
      role of HLA-I alleles in the development of JAK2 V617F-driven MPNs using a 
      population genetics approach. The variability of the HLA-I genotype had no effect 
      on the presence of JAK2 V617F mutation. However, three alleles were found to be 
      inversely correlated with the presence of JAK2 V617F mutation: HLA-A*02:01 
      (p = 0.036), HLA-B*35:01 (p = 0.017), and HLA-C*15:02 (p = 0.033). The 
      HLA-B*35:01 allele was predicted to bind to a 9-mer peptide derived from JAK2 
      V617F mutant protein. Gene expression analysis revealed a lower expression of 
      HLA-A and -B in MPN CD34+ cells compared with normal CD34+ cells, which was 
      modulated by ruxolitinib and interferon-alpha treatment. In summary, we provide 
      robust evidence that specific HLA-I molecules restrict JAK2 V617F-driven 
      oncogenesis. JAK2 V617F+ stem cells evade immune surveillance through 
      downregulation of the HLA-I expression. Therefore, the presence of specific HLA-I 
      alleles might be a predictive marker for response to certain immunotherapies 
      upregulating HLA-I expression. Finally, our findings have implications in the 
      development of mutational neoepitope-based vaccines in MPNs.
CI  - Copyright (c) 2020 ISEH -- Society for Hematology and Stem Cells. Published by 
      Elsevier Inc. All rights reserved.
FAU - Ivanova, Milena
AU  - Ivanova M
AD  - Department of Clinical Immunology, University Hospital Alexandrovska, Medical 
      University, Sofia, Bulgaria.
FAU - Tsvetkova, Gergana
AU  - Tsvetkova G
AD  - Department of Clinical Hematology, University Hospital Alexandrovska, Medical 
      University, Sofia, Bulgaria.
FAU - Lukanov, Tsvetelin
AU  - Lukanov T
AD  - Department of Clinical Immunology, University Hospital Alexandrovska, Medical 
      University, Sofia, Bulgaria.
FAU - Stoimenov, Angel
AU  - Stoimenov A
AD  - Laboratory of Transfusion Medicine, Sofiamed University Hospital, Sofia, 
      Bulgaria.
FAU - Hadjiev, Evgueniy
AU  - Hadjiev E
AD  - Department of Clinical Hematology, University Hospital Alexandrovska, Medical 
      University, Sofia, Bulgaria.
FAU - Shivarov, Velizar
AU  - Shivarov V
AD  - Laboratory of Clinical Immunology, Sofiamed University Hospital, Sofia, Bulgaria; 
      Department of Clinical Hematology, Sofiamed University Hospital, Sofia, Bulgaria; 
      Department of Genetics, Faculty of Biology, St. Kliment Ohridski Sofia 
      University, Sofia, Bulgaria. Electronic address: vshivarov@abv.bg.
LA  - eng
PT  - Journal Article
PT  - Research Support, U.S. Gov't, Non-P.H.S.
DEP - 20201002
PL  - Netherlands
TA  - Exp Hematol
JT  - Experimental hematology
JID - 0402313
RN  - 0 (Histocompatibility Antigens Class I)
RN  - EC 2.7.10.2 (JAK2 protein, human)
RN  - EC 2.7.10.2 (Janus Kinase 2)
SB  - IM
MH  - *Alleles
MH  - Amino Acid Substitution
MH  - *Carcinogenesis/genetics/immunology
MH  - *Hematologic Neoplasms/genetics/immunology
MH  - *Histocompatibility Antigens Class I/genetics/immunology
MH  - Humans
MH  - *Janus Kinase 2/genetics/immunology
MH  - *Mutation, Missense
MH  - *Myeloproliferative Disorders/genetics/immunology
EDAT- 2020/10/06 06:00
MHDA- 2021/01/15 06:00
CRDT- 2020/10/05 20:06
PHST- 2020/05/06 00:00 [received]
PHST- 2020/09/25 00:00 [revised]
PHST- 2020/09/27 00:00 [accepted]
PHST- 2020/10/06 06:00 [pubmed]
PHST- 2021/01/15 06:00 [medline]
PHST- 2020/10/05 20:06 [entrez]
AID - S0301-472X(20)30565-8 [pii]
AID - 10.1016/j.exphem.2020.09.200 [doi]
PST - ppublish
SO  - Exp Hematol. 2020 Dec;92:75-88.e10. doi: 10.1016/j.exphem.2020.09.200. Epub 2020 
      Oct 2.