RECQL5 Suppresses Oncogenic JAK2-Induced Replication Stress and Genomic Instability

JAK2V617F is the most common oncogenic lesion in patients with myeloproliferative neoplasms (MPNs). Despite the ability of JAK2V617F to instigate DNA damage in vitro, MPNs are nevertheless characterized by genomic stability. In this study, we address this paradox by identifying the DNA helicase RECQL5 as a suppressor of genomic instability in MPNs. We report increased RECQL5 expression in JAK2V617F-expressing cells and demonstrate that RECQL5 is required to counteract JAK2V617F-induced replication stress. Moreover, RECQL5 depletion sensitizes JAK2V617F mutant cells to hydroxyurea (HU), a pharmacological inducer of replication stress and the most common treatment for MPNs. Using single-fiber chromosome combing, we show that RECQL5 depletion in JAK2V617F mutant cells impairs replication dynamics following HU treatment, resulting in increased double-stranded breaks and apoptosis. Cumulatively, these findings identify RECQL5 as a critical regulator of genome stability in MPNs and demonstrate that replication stress-associated cytotoxicity can be amplified specifically in JAK2V617F mutant cells through RECQL5-targeted synthetic lethality. [Display omitted] •RECQL5 is upregulated in JAK2V617F mutant erythroblasts in MPN patients•RECQL5 is a target of activated JAK2-PI3K signaling•RECQL5 stabilizes stalled forks during JAK2V617F-associated replication stress•RECQL5 depletion sensitizes JAK2V617F-expressing cells to hydroxyurea Oncogenic JAK2 signaling in MPN patients leads to DNA damage, yet MPNs are characterized by genomic stability. Chen et al. show that the DNA helicase RECQL5 maintains genomic integrity in response to JAK2V617F-associated replication stress. Moreover, RECQL5 depletion sensitizes JAK2V617F-mutant cells to hydroxyurea, the most common treatment for MPN.