JAK2-V617F and interferon-alpha induce megakaryocyte-biased stem cells characterized by decreased long-term functionality

Kód výsledku v IS VaVaI

<a href="https://www.isvavai.cz/riv?ss=detail&h=RIV%2F61989592%3A15110%2F21%3A73610669" target="_blank" >RIV/61989592:15110/21:73610669 - isvavai.cz</a>

Výsledek na webu

<a href="https://ashpublications.org/blood/article/137/16/2139/475343/JAK2-V617F-and-interferon-induce-megakaryocyte" target="_blank" >https://ashpublications.org/blood/article/137/16/2139/475343/JAK2-V617F-and-interferon-induce-megakaryocyte</a>

DOI - Digital Object Identifier

<a href="http://dx.doi.org/10.1182/blood.2020005563" target="_blank" >10.1182/blood.2020005563</a>

Jazyk výsledku

angličtina

Název v původním jazyce

JAK2-V617F and interferon-alpha induce megakaryocyte-biased stem cells characterized by decreased long-term functionality

Popis výsledku v původním jazyce

We studied a subset of hematopoietic stem cells (HSCs) that are defined by elevated expression of CD41 (CD41(hi)) and showed bias for differentiation toward megakaryocytes (Mks). Mouse models of myeloproliferative neoplasms (MPNs) expressing JAK2-V617F (VF) displayed increased frequencies and percentages of the CD41(hi) vs CD41(lo) HSCs compared with wild-type controls. An increase in CD41(hi) HSCs that correlated with JAK2-V617F mutant allele burden was also found in bone marrow from patients with MPN. CD41(hi) HSCs produced a higher number of Mk-colonies of HSCs in single-cell cultures in vitro, but showed reduced long-term reconstitution potential compared with CD41(lo) HSCs in competitive transplantations in vivo. RNA expression profiling showed an upregulated cell cycle, Myc, and oxidative phosphorylation gene signatures in CD41(hi) HSCs, whereas CD41(lo) HSCs showed higher gene expression of interferon and the JAK/STAT and TNF alpha/NF kappa B signaling pathways. Higher cell cycle activity and elevated levels of reactive oxygen species were confirmed in CD41(hi) HSCs by flow cytometry. Expression of Epcr, a marker for quiescent HSCs inversely correlated with expression of CD41 in mice, but did not show such reciprocal expression pattern in patients with MPN. Treatment with interferon-alpha further increased the frequency and percentage of CD41(hi) HSCs and reduced the number of JAK2-V617F(+) HSCs in mice and patients with MPN. The shift toward the CD41(hi) subset of HSCs by interferon-alpha provides a possible mechanism of how interferon-alpha preferentially targets the JAK2 mutant clone.

Název v anglickém jazyce

JAK2-V617F and interferon-alpha induce megakaryocyte-biased stem cells characterized by decreased long-term functionality

Popis výsledku anglicky

We studied a subset of hematopoietic stem cells (HSCs) that are defined by elevated expression of CD41 (CD41(hi)) and showed bias for differentiation toward megakaryocytes (Mks). Mouse models of myeloproliferative neoplasms (MPNs) expressing JAK2-V617F (VF) displayed increased frequencies and percentages of the CD41(hi) vs CD41(lo) HSCs compared with wild-type controls. An increase in CD41(hi) HSCs that correlated with JAK2-V617F mutant allele burden was also found in bone marrow from patients with MPN. CD41(hi) HSCs produced a higher number of Mk-colonies of HSCs in single-cell cultures in vitro, but showed reduced long-term reconstitution potential compared with CD41(lo) HSCs in competitive transplantations in vivo. RNA expression profiling showed an upregulated cell cycle, Myc, and oxidative phosphorylation gene signatures in CD41(hi) HSCs, whereas CD41(lo) HSCs showed higher gene expression of interferon and the JAK/STAT and TNF alpha/NF kappa B signaling pathways. Higher cell cycle activity and elevated levels of reactive oxygen species were confirmed in CD41(hi) HSCs by flow cytometry. Expression of Epcr, a marker for quiescent HSCs inversely correlated with expression of CD41 in mice, but did not show such reciprocal expression pattern in patients with MPN. Treatment with interferon-alpha further increased the frequency and percentage of CD41(hi) HSCs and reduced the number of JAK2-V617F(+) HSCs in mice and patients with MPN. The shift toward the CD41(hi) subset of HSCs by interferon-alpha provides a possible mechanism of how interferon-alpha preferentially targets the JAK2 mutant clone.

Druh

J_imp - Článek v periodiku v databázi Web of Science

CEP obor

—

OECD FORD obor

30205 - Hematology

Projekt

<a href="/cs/project/GA17-05988S" target="_blank" >GA17-05988S: Iniciace a progrese myeloproliferativních onemocnění – role patologické aktivace JAK2 v signální dráze erytropoetinového receptoru</a><br>

Návaznosti

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

Rok uplatnění

2021

Kód důvěrnosti údajů

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

Název periodika

Blood

ISSN

0006-4971

e-ISSN

—

Svazek periodika

137

Číslo periodika v rámci svazku

16

Stát vydavatele periodika

US - Spojené státy americké

Počet stran výsledku

13

Strana od-do

2139-2151

Kód UT WoS článku

000646136700008

EID výsledku v databázi Scopus

2-s2.0-85104668157