Novel germline JAK SUP R715T SUP mutation causing PV-like erythrocytosis in 3 generations. Amelioration by Ropeg-Interferon
The result's identifiers
Result code in IS VaVaI
<a href="https://www.isvavai.cz/riv?ss=detail&h=RIV%2F68378050%3A_____%2F24%3A00586895" target="_blank" >RIV/68378050:_____/24:00586895 - isvavai.cz</a>
Result on the web
<a href="https://onlinelibrary.wiley.com/doi/10.1002/ajh.27311" target="_blank" >https://onlinelibrary.wiley.com/doi/10.1002/ajh.27311</a>
DOI - Digital Object Identifier
<a href="http://dx.doi.org/10.1002/ajh.27311" target="_blank" >10.1002/ajh.27311</a>
Alternative languages
Result language
angličtina
Original language name
Novel germline JAK SUP R715T SUP mutation causing PV-like erythrocytosis in 3 generations. Amelioration by Ropeg-Interferon
Original language description
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.
Czech name
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Czech description
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Classification
Type
J<sub>imp</sub> - Article in a specialist periodical, which is included in the Web of Science database
CEP classification
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OECD FORD branch
10601 - Cell biology
Result continuities
Project
Result was created during the realization of more than one project. More information in the Projects tab.
Continuities
P - Projekt vyzkumu a vyvoje financovany z verejnych zdroju (s odkazem do CEP)
Others
Publication year
2024
Confidentiality
S - Úplné a pravdivé údaje o projektu nepodléhají ochraně podle zvláštních právních předpisů
Data specific for result type
Name of the periodical
American Journal of Hematology
ISSN
0361-8609
e-ISSN
1096-8652
Volume of the periodical
99
Issue of the periodical within the volume
7
Country of publishing house
US - UNITED STATES
Number of pages
10
Pages from-to
1220-1229
UT code for WoS article
001204101600001
EID of the result in the Scopus database
2-s2.0-85190944349