An Extensive Network of TET2-Targeting MicroRNAs Regulates Malignant Hematopoiesis

Abstract

Summary The Ten-Eleven-Translocation 2 (TET2) gene, which oxidates 5-methylcytosine in DNA to 5-hydroxylmethylcytosine (5hmC), is a key tumor suppressor frequently mutated in hematopoietic malignancies. However, the molecular regulation of TET2 expression is poorly understood. We show that TET2 is under extensive microRNA (miRNA) regulation and such TET2-targeting is an important pathogenic mechanism in hematopoietic malignancies. Using a high-throughput 3′UTR activity screen, we identify >30 miRNAs that inhibit TET2 expression and cellular 5hmC. Forced expression of TET2-targeting miRNAs in vivo disrupts normal hematopoiesis, leading to hematopoietic expansion and/or myeloid differentiation bias, whereas co-expression of TET2 corrects these phenotypes. Importantly, several TET2-targeting miRNAs, including miR-125b, miR-29b, miR-29c, miR-101, and miR-7, are preferentially overexpressed in TET2-wildtype acute myeloid leukemia. Our results demonstrate the extensive roles of miRNAs in functionally regulating TET2 and cellular 5hmC, and reveal miRNAs with previously unrecognized oncogenic potential. Our work suggests that TET2-targeting miRNAs might be exploited in cancer diagnosis.

miR-29b Mediates NF-κB Signaling in KRAS-Induced Non–Small Cell Lung Cancers

“…It also negatively regulates proliferation and migration by targeting genes involved in the regulation of the extracellular matrix and restores erroneous promoter methylation by targeting DNMT3A and 3B. On the other hand, miR-29b or its paralogs promote tumor progression, apoptosis resistance, and metastasis of hematologic malignancies and solid cancers by targeting key tumor suppressors, including PTEN, TET2, or proapoptotic genes (34)(35)(36). The molecular mechanisms that determine whether a miRNA is tumorigenic or antitumorigenic are largely unknown.…”

IL-1β-Mediated Repression of microRNA-101 Is Crucial for Inflammation-Promoted Lung Tumorigenesis

“…For instance, miR-101 has been reported to repress malignant transformation and cancer progression by targeting Mcl-1, Stmn1, Junb, and Cxcr7 in hepatocellular carcinoma (22,27), Mycn in neuroblastoma (25), Ezh2 in prostate cancer (23), Cox2 in colon cancer (21), and Mitf and Ezh2 in melanoma (26). Intriguingly, a recent study found that miR-101 represses TET2 and surprisingly shows an oncogenic potential in malignant hematopoiesis (42). Nevertheless, the precise role of miR-101 in NSCLC remained largely unclear.…”

Regulation and Functional Significance of 5-Hydroxymethylcytosine in Cancer

“…miR-22 that targets all three TET and reduces 5hmC levels especially in the loci of mir-200 favors cancer progression and metastasis in breast cancer [42]. Cheng et al reported more than 30 miRNAs that inhibit TET2 regulating hematopoiesis of wild-type AML [73]. TET1 targeting miRNAs like miR-520b, miR-494 in HCC and miR-191 are elevated in intrahepatic cholangiocarcinoma favoring proliferation, migration and invasion [74][75][76].…”