PD-L1 overexpression correlates with JAK2-V617F mutational burden and is associated with 9p uniparental disomy in myeloproliferative neoplasms.

Autor: Milosevic Feenstra JD; Ludwig Boltzmann Institute for Hematology and Oncology, Medical University of Vienna, Vienna, Austria., Jäger R; Department of Laboratory Medicine, Medical University of Vienna, Vienna, Austria., Schischlik F; Cancer Data Science Laboratory, Center for Cancer Research, National Cancer Institute, Bethesda, Maryland, USA., Ivanov D; Department of Internal Medicine I, Division of Hematology and Hemostaseology, Medical University of Vienna, Vienna, Austria., Eisenwort G; Ludwig Boltzmann Institute for Hematology and Oncology, Medical University of Vienna, Vienna, Austria.; Department of Internal Medicine I, Division of Hematology and Hemostaseology, Medical University of Vienna, Vienna, Austria., Rumi E; Department of Molecular Medicine, University of Pavia, Pavia, Italy.; Division of Hematology, Fondazione IRCCS Policlinico San Matteo, Pavia, Italy., Schuster M; CeMM Research Center for Molecular Medicine of the Austrian Academy of Sciences, Vienna, Austria., Gisslinger B; Department of Internal Medicine I, Division of Hematology and Hemostaseology, Medical University of Vienna, Vienna, Austria., Machherndl-Spandl S; Department of Haematology, Internal Oncology and Stem Cell Transplantation, Ordensklinikum Linz Elisabethinen Hospital, Linz, Austria., Bettelheim P; Department of Haematology, Internal Oncology and Stem Cell Transplantation, Ordensklinikum Linz Elisabethinen Hospital, Linz, Austria., Krauth MT; Ludwig Boltzmann Institute for Hematology and Oncology, Medical University of Vienna, Vienna, Austria.; Department of Internal Medicine I, Division of Hematology and Hemostaseology, Medical University of Vienna, Vienna, Austria., Keil F; Ludwig Boltzmann Institute for Hematology and Oncology, Medical University of Vienna, Vienna, Austria.; 3rd Medical Department, Hematology & Oncology, Hanuschkrankenhaus, Vienna, Austria., Bock C; CeMM Research Center for Molecular Medicine of the Austrian Academy of Sciences, Vienna, Austria.; Institute of Artificial Intelligence, Center for Medical Statistics, Informatics, and Intelligent Systems, Medical University of Vienna, Vienna, Austria., Cazzola M; Department of Molecular Medicine, University of Pavia, Pavia, Italy.; Division of Hematology, Fondazione IRCCS Policlinico San Matteo, Pavia, Italy., Gisslinger H; Department of Internal Medicine I, Division of Hematology and Hemostaseology, Medical University of Vienna, Vienna, Austria., Kralovics R; Department of Laboratory Medicine, Medical University of Vienna, Vienna, Austria.; CeMM Research Center for Molecular Medicine of the Austrian Academy of Sciences, Vienna, Austria., Valent P; Ludwig Boltzmann Institute for Hematology and Oncology, Medical University of Vienna, Vienna, Austria.; Department of Internal Medicine I, Division of Hematology and Hemostaseology, Medical University of Vienna, Vienna, Austria.
Jazyk: angličtina
Zdroj: American journal of hematology [Am J Hematol] 2022 Apr; Vol. 97 (4), pp. 390-400. Date of Electronic Publication: 2022 Jan 21.
DOI: 10.1002/ajh.26461
Abstrakt: Myeloproliferative neoplasms (MPN) are chronic stem cell disorders characterized by enhanced proliferation of myeloid cells, immune deregulation, and drug resistance. JAK2 somatic mutations drive the disease in 50-60% and CALR mutations in 25-30% of cases. Published data suggest that JAK2-V617F-mutated MPN cells express the resistance-related checkpoint PD-L1. By applying RNA-sequencing on granulocytes of 113 MPN patients, we demonstrate that PD-L1 expression is highest among polycythemia vera patients and that PD-L1 expression correlates with JAK2-V617F mutational burden (R = 0.52; p < .0001). Single nucleotide polymorphism (SNP) arrays showed that chromosome 9p uniparental disomy (UPD) covers both PD-L1 and JAK2 in all MPN patients examined. MPN cells in JAK2-V617F-positive patients expressed higher levels of PD-L1 if 9p UPD was present compared to when it was absent (p < .0001). Moreover, haplotype-based association analyses provided evidence for germline genetic factors at PD-L1 locus contributing to MPN susceptibility independently of the previously described GGCC risk haplotype. We also found that PD-L1 is highly expressed on putative CD34 + CD38 - disease-initiating neoplastic stem cells (NSC) in both JAK2 and CALR-mutated MPN. PD-L1 overexpression decreased upon exposure to JAK2 blockers and BRD4-targeting agents, suggesting a role for JAK2-STAT5-signaling and BRD4 in PD-L1 expression. Whether targeting of PD-L1 can overcome NSC resistance in MPN remains to be elucidated in forthcoming studies.
(© 2022 The Authors. American Journal of Hematology published by Wiley Periodicals LLC.)
Databáze: MEDLINE
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