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

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‐muta...

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Autores principales: Milosevic Feenstra, Jelena D., Jäger, Roland, Schischlik, Fiorella, Ivanov, Daniel, Eisenwort, Gregor, Rumi, Elisa, Schuster, Michael, Gisslinger, Bettina, Machherndl‐Spandl, Sigrid, Bettelheim, Peter, Krauth, Maria‐Theresa, Keil, Felix, Bock, Christoph, Cazzola, Mario, Gisslinger, Heinz, Kralovics, Robert, Valent, Peter
Formato: Online Artículo Texto
Lenguaje:English
Publicado: John Wiley & Sons, Inc. 2022
Materias:
Acceso en línea:https://www.ncbi.nlm.nih.gov/pmc/articles/PMC9306481/
https://www.ncbi.nlm.nih.gov/pubmed/35015307
http://dx.doi.org/10.1002/ajh.26461
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author Milosevic Feenstra, Jelena D.
Jäger, Roland
Schischlik, Fiorella
Ivanov, Daniel
Eisenwort, Gregor
Rumi, Elisa
Schuster, Michael
Gisslinger, Bettina
Machherndl‐Spandl, Sigrid
Bettelheim, Peter
Krauth, Maria‐Theresa
Keil, Felix
Bock, Christoph
Cazzola, Mario
Gisslinger, Heinz
Kralovics, Robert
Valent, Peter
author_facet Milosevic Feenstra, Jelena D.
Jäger, Roland
Schischlik, Fiorella
Ivanov, Daniel
Eisenwort, Gregor
Rumi, Elisa
Schuster, Michael
Gisslinger, Bettina
Machherndl‐Spandl, Sigrid
Bettelheim, Peter
Krauth, Maria‐Theresa
Keil, Felix
Bock, Christoph
Cazzola, Mario
Gisslinger, Heinz
Kralovics, Robert
Valent, Peter
author_sort Milosevic Feenstra, Jelena D.
collection PubMed
description 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.
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spelling pubmed-93064812022-07-28 PD‐L1 overexpression correlates with JAK2‐V617F mutational burden and is associated with 9p uniparental disomy in myeloproliferative neoplasms Milosevic Feenstra, Jelena D. Jäger, Roland Schischlik, Fiorella Ivanov, Daniel Eisenwort, Gregor Rumi, Elisa Schuster, Michael Gisslinger, Bettina Machherndl‐Spandl, Sigrid Bettelheim, Peter Krauth, Maria‐Theresa Keil, Felix Bock, Christoph Cazzola, Mario Gisslinger, Heinz Kralovics, Robert Valent, Peter Am J Hematol Research Articles 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. John Wiley & Sons, Inc. 2022-01-21 2022-04 /pmc/articles/PMC9306481/ /pubmed/35015307 http://dx.doi.org/10.1002/ajh.26461 Text en © 2022 The Authors. American Journal of Hematology published by Wiley Periodicals LLC. https://creativecommons.org/licenses/by/4.0/This is an open access article under the terms of the http://creativecommons.org/licenses/by/4.0/ (https://creativecommons.org/licenses/by/4.0/) License, which permits use, distribution and reproduction in any medium, provided the original work is properly cited.
spellingShingle Research Articles
Milosevic Feenstra, Jelena D.
Jäger, Roland
Schischlik, Fiorella
Ivanov, Daniel
Eisenwort, Gregor
Rumi, Elisa
Schuster, Michael
Gisslinger, Bettina
Machherndl‐Spandl, Sigrid
Bettelheim, Peter
Krauth, Maria‐Theresa
Keil, Felix
Bock, Christoph
Cazzola, Mario
Gisslinger, Heinz
Kralovics, Robert
Valent, Peter
PD‐L1 overexpression correlates with JAK2‐V617F mutational burden and is associated with 9p uniparental disomy in myeloproliferative neoplasms
title PD‐L1 overexpression correlates with JAK2‐V617F mutational burden and is associated with 9p uniparental disomy in myeloproliferative neoplasms
title_full PD‐L1 overexpression correlates with JAK2‐V617F mutational burden and is associated with 9p uniparental disomy in myeloproliferative neoplasms
title_fullStr PD‐L1 overexpression correlates with JAK2‐V617F mutational burden and is associated with 9p uniparental disomy in myeloproliferative neoplasms
title_full_unstemmed PD‐L1 overexpression correlates with JAK2‐V617F mutational burden and is associated with 9p uniparental disomy in myeloproliferative neoplasms
title_short PD‐L1 overexpression correlates with JAK2‐V617F mutational burden and is associated with 9p uniparental disomy in myeloproliferative neoplasms
title_sort pd‐l1 overexpression correlates with jak2‐v617f mutational burden and is associated with 9p uniparental disomy in myeloproliferative neoplasms
topic Research Articles
url https://www.ncbi.nlm.nih.gov/pmc/articles/PMC9306481/
https://www.ncbi.nlm.nih.gov/pubmed/35015307
http://dx.doi.org/10.1002/ajh.26461
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