Inflammatory and oncogenic signaling, both known to challenge genome stability, are key drivers of BCR-ABL-positive chronic myeloid leukemia (CML) and JAK2 V617F-positive chronic myeloproliferative neoplasms (MPNs). Despite similarities in chronic inflammation and oncogene signaling, major differences in disease course exist. Although BCR-ABL has robust transformation potential, JAK2 V617F-positive polycythemia vera (PV) is characterized by a long and stable latent phase. These differences reflect increased genomic instability of BCR-ABL-positive CML, compared to genome-stable PV with rare cytogenetic abnormalities. Recent studies have implicated BCR-ABL in the development of a "mutator" phenotype fueled by high oxidative damage, deficiencies of DNA repair, and defective ATR-Chk1-dependent genome surveillance, providing a fertile ground for variants compromising the ATM-Chk2-p53 axis protecting chronic phase CML from blast crisis. Conversely, PV cells possess multiple JAK2 V617F-dependent protective mechanisms, which ameliorate replication stress, inflammation-mediated oxidative stress and stress-activated protein kinase signaling, all through up-regulation of RECQL5 helicase, reactive oxygen species buffering system, and DUSP1 actions. These attenuators of genome instability then protect myeloproliferative progenitors from DNA damage and create a barrier preventing cellular stress-associated myelofibrosis. Therefore, a better understanding of BCR-ABL and JAK2 V617F roles in the DNA damage response and disease pathophysiology can help to identify potential dependencies exploitable for therapeutic interventions.

Department of Biology Faculty of Medicine and Dentistry Palacky University 77515 Olomouc Czech Republic

Department of Hemato Oncology University Hospital and Faculty of Medicine and Dentistry Palacky University 77520 Olomouc Czech Republic

Department of Histology and Embryology Faculty of Medicine and Dentistry Palacky University 77515 Olomouc Czech Republic

Division of Genome Biology Department of Biochemistry and Biophysics Science for Life Laboratory Karolinska Institute SE 171 77 Stockholm Sweden

Genome Integrity Unit Danish Cancer Society Research Center DK 2100 Copenhagen Denmark

Institute of Molecular and Translational Medicine Faculty of Medicine and Dentistry Palacky University 77900 Olomouc Czech Republic

Laboratory of Genome Integrity Institute of Molecular Genetics of the ASCR 14220 Prague Czech Republic

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