Počet záznamů: 1
Addiction to DUSP1 protects JAK2V617F-driven polycythemia vera progenitors against inflammatory stress and DNA damage, allowing chronic proliferation
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SYSNO ASEP 0523081 Druh ASEP J - Článek v odborném periodiku Zařazení RIV J - Článek v odborném periodiku Poddruh J Článek ve WOS Název Addiction to DUSP1 protects JAK2V617F-driven polycythemia vera progenitors against inflammatory stress and DNA damage, allowing chronic proliferation Tvůrce(i) Stetka, J. (CZ)
Vyhlidalova, P. (CZ)
Láníková, Lucie (UMG-J)
Koralkova, P. (CZ)
Gursky, J. (CZ)
Hlusi, A. (CZ)
Flodr, P. (CZ)
Hubáčková, Soňa (BTO-N)
Bártek, Jiří (UMG-J) RID
Hodný, Zdeněk (UMG-J) RID
Divoky, V. (CZ)Celkový počet autorů 11 Zdroj.dok. Oncogene. - : Springer - ISSN 0950-9232
Roč. 38, č. 28 (2019), s. 5627-5642Poč.str. 16 s. Forma vydání Online - E Jazyk dok. eng - angličtina Země vyd. GB - Velká Británie Klíč. slova stem-cell function ; reactive oxygen ; replication stress ; oxidative stress ; hematopoietic progenitors ; ifn-gamma ; expression ; disease ; activation ; progression Vědní obor RIV EB - Genetika a molekulární biologie Obor OECD Cell biology Vědní obor RIV – spolupráce Biotechnologický ústav - Genetika a molekulární biologie CEP LTAUSA17142 GA MŠMT - Ministerstvo školství, mládeže a tělovýchovy Způsob publikování Open access Institucionální podpora UMG-J - RVO:68378050 ; BTO-N - RVO:86652036 UT WOS 000474845100006 DOI 10.1038/s41388-019-0813-7 Anotace 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. Pracoviště Ústav molekulární genetiky Kontakt Nikol Škňouřilová, nikol.sknourilova@img.cas.cz, Tel.: 241 063 217 Rok sběru 2020 Elektronická adresa https://www.nature.com/articles/s41388-019-0813-7
Počet záznamů: 1