MYBL2 supports DNA double strand break repair in haematopoietic stem cells

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MYBL2 supports DNA double strand break repair in haematopoietic stem cells. / Bayley, Rachel; Blakemore, Daniel; Cancian, Laila; Dumon, Stephanie; Volpe, Giacomo; Ward, Carl; Al Maghrabi, Ruba; Gujar, Jidnyasa; Reeve, Natasha; Raghavan, Manoj; Higgs, Martin; Stewart, Grant; Petermann, Eva; Garcia, Paloma.

In: Cancer Research, Vol. 78, No. 20, 10.2018, p. 5767-5779.

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@article{e9fd439e9a004cdca5792f7afd2789d7,
title = "MYBL2 supports DNA double strand break repair in haematopoietic stem cells",
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 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.",
author = "Rachel Bayley and Daniel Blakemore and Laila Cancian and Stephanie Dumon and Giacomo Volpe and Carl Ward and {Al Maghrabi}, Ruba and Jidnyasa Gujar and Natasha Reeve and Manoj Raghavan and Martin Higgs and Grant Stewart and Eva Petermann and Paloma Garcia",
year = "2018",
month = oct,
doi = "10.1158/0008-5472.CAN-18-0273",
language = "English",
volume = "78",
pages = "5767--5779",
journal = "Cancer Research",
issn = "0008-5472",
publisher = "American Association for Cancer Research",
number = "20",

}

RIS

TY - JOUR

T1 - MYBL2 supports DNA double strand break repair in haematopoietic stem cells

AU - Bayley, Rachel

AU - Blakemore, Daniel

AU - Cancian, Laila

AU - Dumon, Stephanie

AU - Volpe, Giacomo

AU - Ward, Carl

AU - Al Maghrabi, Ruba

AU - Gujar, Jidnyasa

AU - Reeve, Natasha

AU - Raghavan, Manoj

AU - Higgs, Martin

AU - Stewart, Grant

AU - Petermann, Eva

AU - Garcia, Paloma

PY - 2018/10

Y1 - 2018/10

N2 - 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.

AB - 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.

U2 - 10.1158/0008-5472.CAN-18-0273

DO - 10.1158/0008-5472.CAN-18-0273

M3 - Article

VL - 78

SP - 5767

EP - 5779

JO - Cancer Research

JF - Cancer Research

SN - 0008-5472

IS - 20

ER -