Novel germline JAK SUP R715T SUP mutation causing PV-like erythrocytosis in 3 generations. Amelioration by Ropeg-Interferon

0586895 - ÚMG 2025 RIV US eng J - Článek v odborném periodiku
Song, J. - Láníková, Lucie - Kim, S. J. - Papadopoulos, N. - Meznarich, J. - Constantinescu, S. N. - Parsegov, B. - Prchal, J. F. - Prchal, J. T.
Novel germline JAK SUP R715T SUP mutation causing PV-like erythrocytosis in 3 generations. Amelioration by Ropeg-Interferon.
American Journal of Hematology. Roč. 99, č. 7 (2024), s. 1220-1229. ISSN 0361-8609. E-ISSN 1096-8652
Grant CEP: GA MŠMT LX22NPO5102; GA MZd NU21-03-00338; GA ČR(CZ) GA24-11730S
Institucionální podpora: RVO:68378050
Klíčová slova: polycythemia-vera * erythroid progenitors * stem-cell * erythropoiesis * thrombopoietin * hematopoiesis * jak2(v617f) * activation * phenotypes * stat5
Obor OECD: Cell biology
Impakt faktor: 12.8, rok: 2022
Způsob publikování: Open access
https://onlinelibrary.wiley.com/doi/10.1002/ajh.27311

Polycythemia vera (PV) is a clonal disorder arising from the acquired somatic mutations of the JAK2 gene, including JAK2(V617F) or several others in exon 12. A 38-year-old female had a stroke at age 32 and found to have elevated hemoglobin, normal leukocytes, normal platelets, and tested negative for JAK2(V617F) and exon 12 mutations. Next generation sequencing revealed a novel mutation: JAK2(R715T) in the pseudokinase domain (JH2) at 47.5%. Its presence in her nail DNA confirmed a germline origin. Her mother and her son similarly had erythrocytosis and a JAK2(R715T) mutation. Computer modeling indicated gain-of-function JAK2 activity. The propositus and her mother had polyclonal myelopoiesis, ruling out another somatic mutation-derived clonal hematopoiesis. Some erythroid progenitors of all three generations grew without erythropoietin, a hallmark of PV. The in vitro reporter assay confirmed increased activity of the JAK2(R715T) kinase. Similar to PV, the JAK2(R715T) native cells have increased STAT5 phosphorylation, augmented transcripts of prothrombotic and inflammatory genes, and decreased KLF2 transcripts. The propositus was not controlled by hydroxyurea, and JAK2 inhibitors were not tolerated, however, Ropeginterferon-alfa-2b (Ropeg-IFN-alpha) induced a remission. Ropeg-IFN-alpha treatment also reduced JAK2 activity in the propositus, her mother and JAK2(V617F) PV subjects. We report dominantly inherited erythrocytosis secondary to a novel germline JAK2(R715T) gain-of-function mutation with many but not all comparable molecular features to JAK2(V617F) PV. We also document a previously unreported inhibitory mechanism of JAK2 signaling by Ropeg-IFN-alpha.
Trvalý link: https://hdl.handle.net/11104/0354268