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

Abstract

Aberrant methylation of tumour suppressor genes is associated with the progression to a blast crisis in chronic myeloid leukaemia (CML). Methyl-CpG-binding domain protein 2 (MBD2) has been studied as a "reader" of DNA methylation in many cancers, but its role in CML is unclear. We constructed cell models of a homozygous deletion mutation of MBD2 using gene-editing technology in K562 cells and BV173 cells. Here, we demonstrated that the deletion of MBD2 inhibited cell proliferation capacity in vitro. MBD2 deletion also significantly inhibited K562 cell proliferation in a xenograft tumour model in vivo. Additionally, the JAK2/STAT3 signalling pathway, which is abnormally active in CML, was inhibited by MBD2 deletion, and MBD2 deletion could up-regulate the expression of SHP1. In conclusion, our findings suggest that MBD2 is a candidate therapeutic strategy for the CML blast phase.

<p>MBD2 Correlates with a Poor Prognosis and Tumor Progression in Renal Cell Carcinoma</p>

“… 21 MBD2 deletion induces the inactivation of JAK2/STAT3 pathway and suppresses cell proliferation capacity in chronic myeloid leukemia. 26 MBD2 −/- is protective against the carcinogenesis and tumor progression and significantly suppresses the intestinal tumorigenesis in Apc Min/+ mice. 39 Devailly et al reported that MBD2 is enriched in the methylated regions of target genes and associated with the transcriptional silencing during malignant transformation of human mammary cells.…”

“…Together, MBD2 conferred on cells tumor malignant properties, promoted the cell proliferation, cycle progress, migration and invasion and regulates the proliferation and metastasis-related proteins in RCC, which is consistent with the previous reports of supporting cancer-promoting role of MBD2 in glioma, 22 hepatocellular carcinoma, 24 chronic myeloid leukemia. 26 The exact molecular mechanisms of MBD2 affecting the proliferation, migration and invasion of RCC cells need to be further explored.…”

“…Aberrant DNA methylation modifications are frequently detected in various tumors, and the main mechanisms for DNA methylation-involved tumorigenesis are that methylation levels of the promoter region of anti-oncogene are elevated, which promotes the key anti-oncogene silencing and drives tumorigenesis. 12,[14][15][16] MBD2 has been reported in multiple human malignancies, including gastric cancer, 17 breast cancer, 18,19 colorectal cancer, 20 glioblastoma, 21,22 hilar cholangiocarcinoma, 23 hepatocellular carcinoma, 24,25 chronic myeloid leukemia 26 and prostate cancer. 27 Previous studies confirmed that MBD2 mediates the transcriptional repression of tumor suppressor genes, such as hTERT, 28 GSTP1, 29 BAI1, 21 p14 ARF /p16 INK4a,30 and 14-3-3sigma, 27 which supports the pivotal role of MBD2 in abnormal epigenetic regulation of tumors.…”

“…22 MBD2 deletion induces the activation of JAK2/STAT3 signaling pathway and inhibits tumor growth in chronic myeloid leukemia. 26 Increased MBD2 is proposed as an independent prognostic factor for overall (OS) and disease-free survival (DFS) for hepatocellular carcinoma patients. 24 LOC105369748 upregulates MBD2 through binding to miR-5095, which conveys oncogenic signals to accelerate the carcinogenesis and progression of hepatocellular carcinoma.…”

Expression and clinical significance of methyl‑CpG binding domain protein 2 in high‑grade serous ovarian cancer

“…Knockout of MBD2 upregulates the expression of tumor suppressor genes, such as p16 and p14 ( 33 , 34 ). MBD2 overexpression has been detected in a variety of solid tumors, including HCC, breast cancer, GBM and chronic myeloid leukemia ( 16 – 18 , 35 ). MBD2 promotes breast cancer progression by mediating tumor suppressor gene silencing ( 22 , 36 ).…”