Seven supplementary figures. Figure S1. Proliferation capacity of expanded CD34+ cells purified from MDS patient PBMC samples.Figure S2. Absolute numbers of bone marrow stem cell subpopulations in wild type and Mybl2 deficient animals.Figure S3. Recruitment of 53BP1 after irradiation in Mybl2 deficient HSC. Figure S4. Cell cycle status of bone marrow stem cell subpopulations in wild type and Mybl2 deficient animals. Figure S5. Proliferation and apoptosis of bone marrow stem cell subpopulations in wild type and Mybl2 deficient animals post-irradiation. Figure S6. Effect of ATM inhibition on 53BP1 foci and colony formation in wild type and MYBL2 deficient HSC. Figure S7. The G2M checkpoint in response to irradiation is ATM-dependent in MYBL2 deficient HSC.
ARTICLE 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 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 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 MYBL2 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.Significance: These findings suggest MYBL2 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.Graphical Abstract: http://cancerres.aacrjournals.org/content/canres/78/20/5767/F1.large.jpg. Cancer Res; 78(20); 5767–79. ©2018 AACR.
