JAK2V617F promotes replication fork stalling with disease-restricted impairment of the intra-S checkpoint response.

Journal article

Cancers result from the accumulation of genetic lesions, but the cellular consequences of driver mutations remain unclear, especially during the earliest stages of malignancy. The V617F mutation in the JAK2 non-receptor tyrosine kinase (JAK2V617F) is present as an early somatic event in most patients with myeloproliferative neoplasms (MPNs), and the study of these chronic myeloid malignancies provides an experimentally tractable approach to understanding early tumorigenesis. Introduction of exogenous JAK2V617F impairs replication fork progression and is associated with activation of the intra-S checkpoint, with both effects mediated by phosphatidylinositide 3-kinase (PI3K) signaling. Analysis of clonally derived JAK2V617F-positive erythroblasts from MPN patients also demonstrated impaired replication fork progression accompanied by increased levels of replication protein A (RPA)-containing foci. However, the associated intra-S checkpoint response was impaired in erythroblasts from polycythemia vera (PV) patients, but not in those from essential thrombocythemia (ET) patients. Moreover, inhibition of p53 in PV erythroblasts resulted in more gamma-H2Ax (γ-H2Ax)-marked double-stranded breaks compared with in like-treated ET erythroblasts, suggesting the defective intra-S checkpoint function seen in PV increases DNA damage in the context of attenuated p53 signaling. These results demonstrate oncogene-induced impairment of replication fork progression in primary cells from MPN patients, reveal unexpected disease-restricted differences in activation of the intra-S checkpoint, and have potential implications for the clonal evolution of malignancies.

Authors: Chen, E; Ahn, J; Massie, C; Clynes, D; Godfrey, A

• Publication status: Published
• Publisher: National Academy of Sciences
• Journal: Proceedings of the National Academy of Sciences of the United States of America
• Volume: 111
• Issue: 42
• Pages: 15190-15195
• Publication date: 2014-10-01
• DOI: 10.1073/pnas.1401873111
• EISSN: 1091-6490
• ISSN: 0027-8424
• Language: English
• Keywords: myeloproliferative neoplasm; replication stress; JAK2V617F