Year: 2015
Type: article
Abstract: 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.
Source: Cell Reports
Authors: Edwin Chen, Jong Sook Ahn, David B. Sykes, Lawrence J. Breyfogle, Anna L. Godfrey, Jyoti Nangalia, Amy Ko, Daniel J. DeAngelo, Anthony R. Green, Ann Mullally
Institutions: Broad Institute, Brigham and Women's Hospital, Harvard University, Massachusetts Institute of Technology, Wellcome/MRC Cambridge Stem Cell Institute, University of Cambridge, Addenbrooke's Hospital, Wellcome Trust, Medical Research Council, Massachusetts General Hospital, Dana-Farber Cancer Institute, Dana-Farber Brigham Cancer Center
Language: English
Subfield: Genetics (clinical)
Field: Medicine
Domain: Health Sciences
Open Access status: gold
Estimated APC paid: $5,620
OpenAlex ID: W2189634335