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

0559938 - ÚMG 2023 RIV CH eng J - Článek v odborném periodiku
Stetka, J. - Gursky, J. - Velasquez, J.L. - Mojzikova, R. - Vyhlidalova, P. - Vrablova, L. - Bártek, Jiří - Divoký, V.
Role of DNA Damage Response in Suppressing Malignant Progression of Chronic Myeloid Leukemia and Polycythemia Vera: Impact of Different Oncogenes.
Cancers (Basel). Roč. 12, č. 4 (2020), č. článku 903. E-ISSN 2072-6694
Grant CEP: GA MŠMT(CZ) LM2018126; GA MŠMT ED2.1.00/19.0395; GA MŠMT(CZ) ED1.1.00/02.0109; GA ČR GA17-05988S
Institucionální podpora: RVO:68378050
Klíčová slova: DNA damage response * chronic myeloid leukemia * polycythemia vera * ATM-Chk2 pathway
Obor OECD: Oncology
Impakt faktor: 6.639, rok: 2020
Způsob publikování: Open access
https://www.mdpi.com/2072-6694/12/4/903

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.
Trvalý link: https://hdl.handle.net/11104/0333058