MBD2 Ablation Impairs Lymphopoiesis and Impedes Progression and Maintenance of T-ALL

Abstract

Aberrant DNA methylation patterns in leukemia might be exploited for therapeutic targeting. In this study, we employed a genetically deficient mouse model to explore the role of the methylated DNA binding protein MBD2 in normal and malignant hematopoiesis. MBD2 ablation led to diminished lymphocytes. Functional defects of the lymphoid compartment were also observed after reconstitution of MBD2-deficient hematopoietic stem cells (HSC). In an established model of Notch1-driven T-cell acute lymphoblastic leukemia (T-ALL), MBD2 ablation impeded malignant progression and maintenance by attenuating the Wnt signaling pathway. In clinical specimens of human T-ALL, Wnt signaling pathway signatures were significantly enhanced and positively correlated with the expression and function of MBD2. Furthermore, a number of typical Wnt signaling inhibitory genes were abnormally hypermethylated in primary human T-ALL. Abnormal activation of Wnt signaling in T-ALL was switched off by MBD2 deletion, partially by reactivating epigenetically silenced Wnt signaling inhibitors. Taken together, our results define essential roles for MBD2 in lymphopoiesis and T-ALL and suggest MBD2 as a candidate therapeutic target in T-ALL. This study highlights a methylated DNA binding protein as a candidate therapeutic target to improve the treatment of T-cell acute lymphoblastic leukemias, as a new starting point for developing epigenetic therapy in this and other lymphoid malignancies. .

Deletion of MBD2 inhibits proliferation of chronic myeloid leukaemia blast phase cells

“…ChIP assays were performed as previously described. 19 Antibody anti-MBD2 was from Bethyl Laboratories, and isotypic IgG from Beyotime Biotechnology. The DNA Purification Kit (TIANGEN, Beijing, China) was used to purify the coprecipitated DNA.…”

“…[16][17][18] Our previous study defined essential roles for MBD2 in lymphopoiesis and Tcell acute lymphoblastic leukaemia (T-ALL) and suggested MBD2 as a candidate therapeutic target in T-ALL. 19 The expression of MBD2 was high in CML-BP patients. 20 Therefore, we can speculate that MBD2 may be a selective target for CML therapy.…”

MBD2 serves as a viable target against pulmonary fibrosis by inhibiting macrophage M2 program

“…Among these proteins, MBD2 has been shown to have the highest binding activity to methylated CpG DNA. Therefore, MBD2 has been recognized to be involved in the pathogenesis of tumorigenesis (19), autoimmunity (20,21), ischemic injury (22), obesity (17), and neuronal degeneration (23).…”

CD74 is a regulator of hematopoietic stem cell maintenance

“…To further follow CD74 regulated cascades, RNA sequencing (RNAseq) analysis of gene expression in WT and CD74 −/− CD34-LSK cells was performed. RNAseq revealed that CD74 regulated the expression of transcription factors including KLF4, KLF2, and E2F2, and altered the expression of pathways induced by transcription factors such as IRF8, MDB2, and CEBPA, which are known to regulate HSCP maintenance ( S5B Fig) [39][40][41][42][43][44]. The RNAseq also revealed a regulation of the ITGB2 and ITGB3 pathways.…”