MYBL2 supports DNA double strand break repair in haematopoietic stem cells

Rachel Bayley, Daniel Blakemore, Laila Cancian, Stephanie Dumon, Giacomo Volpe, Carl Ward, Ruba Al Maghrabi, Jidnyasa Gujar, Natasha Reeve, Manoj Raghavan, Martin Higgs, Grant Stewart, Eva Petermann, Paloma Garcia

Research output: Contribution to journalArticlepeer-review

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Myelodysplastic syndromes (MDS) are a heterogeneous group of diseases characterized by blood cytopenias that occur as a result of somatic mutations in hematopoietic stem cells (HSC). MDS leads to ineffective haematopoiesis, and as many as 30% of patients progress to acute myeloid leukaemia (AML). The mechanisms by which mutations accumulate in HSC during aging remain poorly understood. Here we identify a novel role for MYBL2 in DNA double-strand break (DSB) repair in HSC. In MDS patients, low MYBL2 levels associated with and preceded transcriptional deregulation of DNA repair genes. Stem/progenitor cells from these patients display dysfunctional DSB repair kinetics after exposure to ionizing radiation (IR). Haploinsufficiency of Mybl2 in mice also led to a defect in the repair of DSB induced by IR in HSC and was characterized by unsustained phosphorylation of the ATM substrate Kap1 and telomere fragility. Our study identifies MYBL2 as a crucial regulator of DSB repair and identifies MYBL2 expression levels as a potential biomarker to predict cellular response to genotoxic treatments in MDS and identify patients with defects in DNA repair. Such patients with worse prognosis may require a different therapeutic regimen to prevent progression to AML.
Original languageEnglish
Pages (from-to)5767-5779
Number of pages13
JournalCancer Research
Issue number20
Early online date6 Aug 2018
Publication statusPublished - 15 Oct 2018


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