Dysfunction of the WT1-MEG3 signaling promotes AML leukemogenesis via p53-dependent and -independent pathways

Abstract

Long non-coding RNAs (lncRNAs) play a pivotal role in tumorigenesis, exemplified by the recent finding that lncRNA maternally expressed gene 3 (MEG3) inhibits tumor growth in a p53-dependent manner. Acute myeloid leukemia (AML) is the most common malignant myeloid disorder in adults, and TP53 mutations or loss are frequently detected in patients with therapy-related AML or AML with complex karyotype. Here, we reveal that MEG3 is significantly downregulated in AML and suppresses leukemogenesis not only in a p53-dependent, but also a p53-independent manner. In addition, MEG3 is proven to be transcriptionally activated by Wilms’ tumor 1 (WT1), dysregulation of which by epigenetic silencing or mutations is causally involved in AML. Therefore MEG3 is identified as a novel target of the WT1 molecule. Ten–eleven translocation-2 (TET2) mutations frequently occur in AML and significantly promote leukemogenesis of this disorder. In our study, TET2, acting as a cofactor of WT1, increases MEG3 expression. Taken together, our work demonstrates that TET2 dysregulated WT1-MEG3 axis significantly promotes AML leukemogenesis, paving a new avenue for diagnosis and treatment of AML patients.

Long non‐coding RNA MEG3 knockdown attenuates endoplasmic reticulum stress‐mediated apoptosis by targeting p53 following myocardial infarction

“…Maternally expressed gene 3 (MEG3) is located in human chromosome 14q32 at a region that approximately covers 1.6 kb nucleotides. This gene was found to act as a tumour suppressor and to possess highly conserved expression in multiple tissues . The expression levels of lncRNA MEG3 were down‐regulated in various types of human tumours, contributing to increase cellular apoptosis via the regulation of p53 protein, microRNA‐127 and microRNA‐21‐5p .…”

“…This gene was found to act as a tumour suppressor and to possess highly conserved expression in multiple tissues. 9,10 The expression levels of lncRNA MEG3 were down-regulated in various types of human tumours, contributing to increase cellular apoptosis via the regulation of p53 protein, microRNA-127 and microRNA-21-5p. [11][12][13] With regard to the cardiovascular system, the knockdown of lncRNA MEG3 could alleviate hypoxia-induced H9c2 cell injury.…”

The DLK1-MEG3 locus in malignant cells of proposed primordial germ cell origins.

“…Thus, high expression of DLK1 in leukemic blasts may promote their accumulation by blocking their differentiation and preventing their uptake of chemotherapeutics through hyperproliferation. This was not reflected in any association between DLK1 expression and the complete remission of patients, but using a larger number of patients and separating them into "high DLK1 expression" and "low expression and either the complete remission or survival of patients, which was unexpected due to the suppressive role previously found for MEG3 in leukemogenesis [62]. Also like DLK1, this could be explained by biallelic expression of MEG3, which has not been thoroughly investigated in AML.…”

“…Decreased expression of MEG3 was also recently implicated in the development of AML [62]. Investigating potential associations between methylation of CpG sites within the DLK1-MEG3 locus and the expression of DLK1, MEG3, and the DLK1/MEG3 expression ratio in AML patients did not reveal any such associations for individual (Figures 18-21) or combined CpG sites (Figures 22, 23).…”

“…Similarly, as the quiescence and stemness maintenance of murine HSCs was determined to be controlled by the Igf2-H19 and Dlk1-Meg3 loci, it is not surprising that the imprinting of these loci is disrupted in AML [5,6,59,60]. The DLK1-MEG3 locus in particular has been extensively studied in MDS and leukemias, where MEG3 was identified as a tumor suppressor in AML and DLK1 was found to inhibit the differentiation and proliferation of promyelocytic cells [61,62]. However, few studies have focused on the potential associations between genes from these paternally imprinted loci and patient outcome.…”