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 IFNγ- and NF-κB-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 DUSP1-inhibited 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.

Danish Cancer Society Research Center DK 2100 Copenhagen Denmark

Department of Biology Faculty of Medicine and Dentistry Palacky University Olomouc Czech Republic

Department of Clinical and Molecular Pathology University Hospital and Faculty of Medicine and Dentistry Palacky University Olomouc Czech Republic

Department of Hemato Oncology University Hospital and Faculty of Medicine and Dentistry Palacky University Olomouc Czech Republic

Department of Histology and Embryology Faculty of Medicine and Dentistry Palacky University Olomouc Czech Republic

Division of Genome Biology Department of Biochemistry and Biophysics Science for Life Laboratory Karolinska Institute Stockholm Sweden

Institute of Molecular and Translational Medicine Faculty of Medicine and Dentistry Palacky University Olomouc Czech Republic

Laboratory of Cell and Developmental Biology Institute of Molecular Genetics of the ASCR v v i Prague Czech Republic

Laboratory of Genome Integrity Institute of Molecular Genetics of the ASCR v v i Prague Czech Republic

Laboratory of Molecular Therapy Institute of Biotechnology BIOCEV Czech Academy of Sciences Prague West 252 50 Czech Republic

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