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National Academy of Sciences, Proceedings of the National Academy of Sciences, 42(111), p. 15190-15195

DOI: 10.1073/pnas.1401873111



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

This paper is made freely available by the publisher.
This paper is made freely available by the publisher.

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Cancers arise through a succession of enabling genetic lesions, but the consequences of many driver mutations remain unclear, especially in the earliest stages of tumor formation. The myeloproliferative neoplasms (MPNs) encompass a group of chronic hematologic disorders that can collectively provide a window into these early stages of leukemia evolution. This study reveals a role for the JAK2V617F mutation, the most frequent genetic abnormality in MPN patients, in impairing replication fork progression during cell division of MPN patient-derived tumor cells. Moreover, analysis of different MPN disease subtypes reveals unexpected differences in DNA repair activity in response to JAK2V617F-induced perturbations in replication dynamics. These findings have potential implications for tumor clonal evolution and individualized cancer therapy.