Addiction to DUSP1 protects JAK2V617F-driven polycythemia vera progenitors against inflammatory stress and DNA damage, allowing chronic proliferation

Result code in IS VaVaI

<a href="https://www.isvavai.cz/riv?ss=detail&h=RIV%2F68378050%3A_____%2F19%3A00523081" target="_blank" >RIV/68378050:_____/19:00523081 - isvavai.cz</a>

Alternative codes found

RIV/86652036:_____/19:00523081 RIV/61989592:15110/19:73596022 RIV/00098892:_____/19:N0000057

Result on the web

<a href="https://www.nature.com/articles/s41388-019-0813-7" target="_blank" >https://www.nature.com/articles/s41388-019-0813-7</a>

DOI - Digital Object Identifier

<a href="http://dx.doi.org/10.1038/s41388-019-0813-7" target="_blank" >10.1038/s41388-019-0813-7</a>

Result language

angličtina

Original language name

Addiction to DUSP1 protects JAK2V617F-driven polycythemia vera progenitors against inflammatory stress and DNA damage, allowing chronic proliferation

Original language description

Inflammatory and oncogenic signaling converge in disease evolution of BCR-ABL-negative myeloproliferative neoplasms, clonal hematopoietic stem cell disorders characterized by gain-of-function mutation in JAK2 kinase (JAK2V617F), with highest prevalence in patients with polycythemia vera (PV). Despite the high risk, DNA-damaging inflammatory microenvironment, PV progenitors tend to preserve their genomic stability over decades until their progression to post-PV myelofibrosis/acute myeloid leukemia. Using induced pluripotent stem cells-derived CD34(+) progenitor-enriched cultures from JAK2V617F(+) PV patient and from JAK2 wild-type healthy control, CRISPR-modified HEL cells and patients' bone marrow sections from different disease stages, we demonstrate that JAK2V617F induces an intrinsic IFN gamma- and NF-kappa B associated inflammatory program, while suppressing inflammation-evoked DNA damage both in vitro and in vivo. We show that cells with JAK2V617F tightly regulate levels of inflammatory cytokines-induced reactive oxygen species, do not fully activate the ATM/p53/p21waf1 checkpoint and p38/JNK MAPK stress pathway signaling when exposed to inflammatory cytokines, suppress DNA single-strand break repair genes' expression yet overexpress the dual-specificity phosphatase (DUSP) 1. RNAi-mediated knock-down and pharmacological inhibition of DUSP1, involved in p38/JNK deactivation, in HEL cells reveals growth addiction to DUSP1, consistent with enhanced DNA damage response and apoptosis in DUSP1inhibited parental JAK2V617F(+) cells, but not in CRISPR-modified JAK2 wild-type cells. Our results indicate that the JAK2V617F+ PV progenitors utilize DUSP1 activity as a protection mechanism against DNA damage accumulation, promoting their proliferation and survival in the inflammatory microenvironment, identifying DUSP1 as a potential therapeutic target in PV.

Czech name

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Czech description

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Type

J_imp - 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

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)

Publication year

2019

Confidentiality

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

Name of the periodical

Oncogene

ISSN

0950-9232

e-ISSN

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Volume of the periodical

38

Issue of the periodical within the volume

28

Country of publishing house

GB - UNITED KINGDOM

Number of pages

16

Pages from-to

5627-5642

UT code for WoS article

000474845100006

EID of the result in the Scopus database

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