Cell Reports
Volume 5, Issue 2, 31 October 2013, Pages 471-481
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Article
An Extensive Network of TET2-Targeting MicroRNAs Regulates Malignant Hematopoiesis

https://doi.org/10.1016/j.celrep.2013.08.050Get rights and content
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Highlights

  • Systematic identification of TET2-targeting miRNAs via high-throughput 3′ UTR screen

  • TET2-targeting miRNAs regulate cellular 5hmC and malignant hematopoiesis

  • TET2 expression corrects microRNA-induced malignant hematopoiesis

  • TET2-targeting miRNAs are more likely to be overexpressed in TET2-wild-type leukemia

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 coexpression 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-wild-type 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.

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This is an open-access article distributed under the terms of the Creative Commons Attribution License, which permits unrestricted use, distribution, and reproduction in any medium, provided the original author and source are credited.

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These authors contributed equally to this work