MYBL2 Supports DNA Double Strand Break Repair in Hematopoietic 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 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 .

WNT inhibition creates a BRCA-like state in Wnt-addicted cancer

“…Transcription factor binding site (TFBS) targets were obtained from the ENCODE, ReMAP, and Literature ChIP-seq datasets using the online tool CHEA3 (39). This analysis identified significant enrichment for FOXM1 and MYBL2 binding events ( Figure 5A) which is consistent with the established roles of these two transcription factors in the regulation of DNA repair pathways (40)(41)(42)(43). We next examined if either of these transcription factors was Wnt-activated.…”

“…MYBL2 is known to regulate cell proliferation, differentiation and tumorigenesis (70, 71). However, its role in regulating the HR and FA pathways has only recently been reported in hematopoietic stem cells (HSCs), where its expression was shown to correlate with the levels of DNA repair genes including RAD51, BRCA1/2 and FANCD2 (42,43). Low levels of MYBL2 in myelodysplastic syndrome (MDS) patients also preceded transcriptional deregulation of DNA repair genes (72).…”

Dependence on Myb expression is attenuated in myeloid leukaemia with N-terminal CEBPA mutations

“…After transfection, the cells were plated at a density of 10 6 cells/ml and viable cells counted and passaged at a ratio of 1:2 every 24 h for 4 consecutive days. Cell cycle analysis was performed by labelling transfected cells (48 h post-nucleofection) with 10 μM BrdU for 1 h. Cells were co-stained with 7-AAD (A9400-1mg; Sigma-Aldrich) and BrdU using the BrdU flow kit (8811-6600; BD Bioscience) according to the manufacturer’s instructions, as previously described (Bayley et al, 2018). Apoptosis analysis was performed using the Annexin V kit (eBioscience) as previously described (Volpe et al, 2015).…”

MYBL2 mRNA expression as a potential biomarker of therapeutic response to genotoxic treatments in myelodysplastic syndrome

“…In particular, identification of molecular markers that affect disease severity would allow the stratification of patients to potentially inform choice of treatment. To this end, our recent work has identified the RNA expression of the MYBL2 gene in HSC as a critical determinant of disease prognosis and DNA double-strand break (DSB) repair in MDS patients [6].…”

“…We have further investigated the mechanisms by which MYBL2 function could contribute to MDS development and uncovered an important role for MYBL2 in DNA DSB repair in HSC [6]. HSC obtained from Mybl2 haploinsufficient animals exhibited significant defects in DSB repair, caused by an inability to maintain ATM-dependent KAP-1 phosphorylation, which resulted in telomere fragility [6]. KAP-1 phosphorylation is essential for the repair of DSBs within regions of heterochromatin, suggesting a role for of Mybl2 within the ATM-dependent DNA damage response (DDR) crucial for maintaining genome stability.…”