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

Kód výsledku v 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>

Výsledek na webu

<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>

Jazyk výsledku

angličtina

Název v původním jazyce

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

Popis výsledku v původním jazyce

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.

Název v anglickém jazyce

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

Popis výsledku anglicky

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.

Druh

J_imp - Článek v periodiku v databázi Web of Science

CEP obor

—

OECD FORD obor

10601 - Cell biology

Projekt

Výsledek vznikl pri realizaci vícero projektů. Více informací v záložce Projekty.

Návaznosti

P - Projekt vyzkumu a vyvoje financovany z verejnych zdroju (s odkazem do CEP)

Rok uplatnění

2024

Kód důvěrnosti údajů

S - Úplné a pravdivé údaje o projektu nepodléhají ochraně podle zvláštních právních předpisů

Název periodika

American Journal of Hematology

ISSN

0361-8609

e-ISSN

1096-8652

Svazek periodika

99

Číslo periodika v rámci svazku

7

Stát vydavatele periodika

US - Spojené státy americké

Počet stran výsledku

10

Strana od-do

1220-1229

Kód UT WoS článku

001204101600001

EID výsledku v databázi Scopus

2-s2.0-85190944349