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Role of DNA Damage Response in Suppressing Malignant Progression of Chronic Myeloid Leukemia and Polycythemia Vera: Impact of Different Oncogenes

1
Department of Biology, Faculty of Medicine and Dentistry, Palacky University, 77515 Olomouc, Czech Republic
2
Department of Histology and Embryology, Faculty of Medicine and Dentistry, Palacky University, 77515 Olomouc, Czech Republic
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Department of Hemato-Oncology, University Hospital and Faculty of Medicine and Dentistry, Palacky University, 77520 Olomouc, Czech Republic
4
Institute of Molecular and Translational Medicine, Faculty of Medicine and Dentistry, Palacky University, 77900 Olomouc, Czech Republic
5
Genome Integrity Unit, Danish Cancer Society Research Center, DK-2100 Copenhagen, Denmark
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Laboratory of Genome Integrity, Institute of Molecular Genetics of the ASCR, 14220 Prague, Czech Republic
7
Division of Genome Biology, Department of Biochemistry and Biophysics, Science for Life Laboratory, Karolinska Institute, SE-171 77 Stockholm, Sweden
*
Authors to whom correspondence should be addressed.
Cancers 2020, 12(4), 903; https://doi.org/10.3390/cancers12040903
Received: 13 March 2020 / Revised: 2 April 2020 / Accepted: 4 April 2020 / Published: 7 April 2020
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. View Full-Text
Keywords: DNA damage response; chronic myeloid leukemia; polycythemia vera; ATM-Chk2 pathway DNA damage response; chronic myeloid leukemia; polycythemia vera; ATM-Chk2 pathway
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Stetka, J.; Gursky, J.; Liñan Velasquez, J.; Mojzikova, R.; Vyhlidalova, P.; Vrablova, L.; Bartek, J.; Divoky, V. Role of DNA Damage Response in Suppressing Malignant Progression of Chronic Myeloid Leukemia and Polycythemia Vera: Impact of Different Oncogenes. Cancers 2020, 12, 903.

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