MYBL2 Supports DNA Double Strand Break Repair in Hematopoietic Stem Cells.

Bayley, Rachel, Blakemore, Daniel, Cancian, Laila, Dumon, Stephanie, Volpe, Giacomo, Ward, Carl, Almaghrabi, Ruba, Gujar, Jidnyasa, Reeve, Natasha, Raghavan, Manoj, Higgs, Martin R, Stewart, Grant S, Petermann, Eva and García, Paloma (2018) MYBL2 Supports DNA Double Strand Break Repair in Hematopoietic Stem Cells. Cancer research, 78 (20). pp. 5767-5779. ISSN 1538-7445. This article is available to all UHB staff and students via ASK Discovery tool http://tinyurl.com/z795c8c by using their UHB Athens login IDs

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Abstract

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 hematopoiesis, and as many as 30% of patients progress to acute myeloid leukemia (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 patients with MDS, low 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 in mice also led to a defect in the repair of DSBs 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 expression levels as a potential biomarker to predict cellular response to genotoxic treatments in MDS and to identify patients with defects in DNA repair. Such patients with worse prognosis may require a different therapeutic regimen to prevent progression to AML. These findings suggest levels may be used as a biological biomarker to determine the DNA repair capacity of hematopoietic stem cells from patients with MDS and as a clinical biomarker to inform decisions regarding patient selection for treatments that target DNA repair. http://cancerres.aacrjournals.org/content/canres/78/20/5767/F1.large.jpg .

Item Type:	Article
Additional Information:	This article is available to all UHB staff and students via ASK Discovery tool http://tinyurl.com/z795c8c by using their UHB Athens login IDs
Subjects:	QW Microbiology. Immunology QZ Pathology. Oncology WH Haemic and lymphatic systems. Haematology
Divisions:	Planned IP Care > Oncology and Clinical Haematology
Related URLs:	https://www.ncbi.nlm.nih.gov/pubmed/3008...
Depositing User:	Beth Connors
Date Deposited:	11 Oct 2019 14:18
Last Modified:	11 Oct 2019 14:18
URI:	http://www.repository.uhblibrary.co.uk/id/eprint/2470

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