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Cell Rep. 2015 Dec 22;13(11):2345-2352. doi: 10.1016/j.celrep.2015.11.037. Epub 2015 Dec 10.

RECQL5 Suppresses Oncogenic JAK2-Induced Replication Stress and Genomic Instability.

Author information

1
Division of Hematology, Department of Medicine, Brigham and Women's Hospital, Harvard Medical School, Boston, MA 02115; Broad Institute of the Massachusetts Institute of Technology and Harvard, 415 Main Street, Cambridge, MA 02142.
2
Cambridge Institute for Medical Research, Medical Research Council/Wellcome Trust Stem Cell Institute, and Department of Haematology, University of Cambridge, Hills Road, Cambridge CB2 0XY, UK; Department of Haematology, Addenbrooke's Hospital, Hills Road, Cambridge CB2 0XY, UK.
3
Center for Regenerative Medicine, Massachusetts General Hospital, 185 Cambridge Street, Boston, MA 02114.
4
Division of Hematology, Department of Medicine, Brigham and Women's Hospital, Harvard Medical School, Boston, MA 02115.
5
Department of Medical Oncology, Dana Farber Cancer Institute, 44 Binney Street, Boston, MA 02115.
6
Division of Hematology, Department of Medicine, Brigham and Women's Hospital, Harvard Medical School, Boston, MA 02115; Broad Institute of the Massachusetts Institute of Technology and Harvard, 415 Main Street, Cambridge, MA 02142; Department of Medical Oncology, Dana Farber Cancer Institute, 44 Binney Street, Boston, MA 02115. Electronic address: amullally@partners.org.

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.

PMID:
26686625
PMCID:
PMC4691544
DOI:
10.1016/j.celrep.2015.11.037
[Indexed for MEDLINE]
Free PMC Article

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