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

0523081 - ÚMG 2020 RIV GB eng J - Článek v odborném periodiku
Stetka, J. - Vyhlidalova, P. - Láníková, Lucie - Koralkova, P. - Gursky, J. - Hlusi, A. - Flodr, P. - Hubáčková, Soňa - Bártek, Jiří - Hodný, Zdeněk - Divoky, V.
Addiction to DUSP1 protects JAK2V617F-driven polycythemia vera progenitors against inflammatory stress and DNA damage, allowing chronic proliferation.
Oncogene. Roč. 38, č. 28 (2019), s. 5627-5642. ISSN 0950-9232. E-ISSN 1476-5594
Grant CEP: GA MŠMT LTAUSA17142
Institucionální podpora: RVO:68378050 ; RVO:86652036
Klíčová slova: stem-cell function * reactive oxygen * replication stress * oxidative stress * hematopoietic progenitors * ifn-gamma * expression * disease * activation * progression
Obor OECD: Cell biology; Cell biology (BTO-N)
Impakt faktor: 7.971, rok: 2019
Způsob publikování: Open access
https://www.nature.com/articles/s41388-019-0813-7

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.
Trvalý link: http://hdl.handle.net/11104/0307482