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조회277

University of Utah

Am. J. Hematol., Apr 17 2024, | https://doi.org/10.1002/ajh.27311 Novel germline JAK2R715T mutation causing PV-like erythrocytosis in 3 generations. Amelioration by Ropeg-Interferon

Jihyun Song¹, Lucie Lanikova², Soo Jin Kim¹, Nicolas Papadopoulos^3,4, Jessica Meznarich⁵, Stefan N. Constantinescu^3,4,6,7, Brynn Parsegov¹, Jaroslav F. Prchal⁸, Josef T. Prchal¹

¹Division of Hematology & Hematologic Malignancies, Huntsman Cancer Institute, University of Utah, Salt Lake City, Utah, USA

²Department of Cell and Developmental Biology, Institute of Molecular Genetics of the Czech Academy of Sciences, Prague, Czech Republic

³Ludwig Institute for Cancer Research, Brussels, Belgium

⁴de Duve Institute, Brussels, Belgium

⁵Division of Hematology-Oncology, Department of Pediatrics, University of Utah and Primary Children's Hospital, Salt Lake City, Utah, USA

⁶Nuffield Department of Medicine, Oxford University, Oxford, UK

⁷WELBIO Department, WEL Research Institute, Wavre, Belgium

⁸McGill University Montreal, Quebec City, Quebec, Canada

Correspondence : Josef T. Prchal

Abstract

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-α) induced a remission. Ropeg-IFN-α 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-α.

논문정보

형식Research article
게재일2024년 04월 (BRIC 등록일 2024-04-19)
연구진국외 연구진
분야 의약학 > 분자세포의학

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