The KDM2B- let-7b -EZH2 axis in myelodysplastic syndromes as a target for combined epigenetic therapy.

摘要: Both DNA and histone methylation are dysregulated in the myelodysplastic syndromes (MDS). Based on preliminary data we hypothesized that interactions of KDM2B, let-7b EZH2 signals lead to an aberrant epigenetic landscape. Gene expression CD34+ cells from MDS marrows was analyzed by NanoString miR array validated real-time polymerase chain reaction (PCR). The functions were characterized myeloid cell lines primary cells. Let-7b levels significantly higher, KDM2B lower marrow (n = 44) than healthy controls 21; p<0.013, p<0.0001, respectively). Overexpression reduced protein levels, decreased S-phase while increasing G0/G1 (p 0.0005), accompanied H3K27me3 cyclin D1. Silencing increased expression. Treatment with cyclopentanyl analog 3-deazaadenosine, DZNep, combined hypomethylating agent 5-azacitidine, EZH2, suppressed di- tri-methylated H3K27, p16 expression, associated proliferation. Thus, via let-7b/EZH2, promotes transcriptional repression. DZNep bypassed inhibitory KDM2B/let-7b/EZH2 axis preventing H3K27 reducing might be able enhance therapeutic effects agents such as currently considered standard therapy for patients MDS.