An Extensive Network of TET2-Targeting MicroRNAs Regulates Malignant Hematopoiesis

• Published in: Cell reports (Cambridge) 2013-10, Vol.5 (2), p.471-481
• Main Authors: Cheng, Jijun, Guo, Shangqin, Chen, Suning, Mastriano, Stephen J., Liu, Chaochun, D’Alessio, Ana C., Hysolli, Eriona, Guo, Yanwen, Yao, Hong, Megyola, Cynthia M., Li, Dan, Liu, Jun, Pan, Wen, Roden, Christine A., Zhou, Xiao-Ling, Heydari, Kartoosh, Chen, Jianjun, Park, In-Hyun, Ding, Ye, Zhang, Yi, Lu, Jun
• Format: Article
• Language: English
• Subjects: 3' Untranslated Regions; 5-Methylcytosine - analogs & derivatives; Animals; Cytosine - analogs & derivatives; Cytosine - metabolism; Dioxygenases; DNA-Binding Proteins - genetics; DNA-Binding Proteins - metabolism; Down-Regulation; Hematologic Neoplasms - genetics; Hematologic Neoplasms - metabolism; Hematologic Neoplasms - pathology; Hematopoiesis; Humans; Mice; MicroRNAs - metabolism; Phenotype; Proto-Oncogene Proteins - genetics; Proto-Oncogene Proteins - metabolism
• ISSN: 2211-1247; 2211-1247
• DOI: 10.1016/j.celrep.2013.08.050

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. [Display omitted] •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 Mutations that compromise the function of TET2 or its regulatory proteins lead to hematopoietic malignancies. Lu, Guo, and colleagues now show that an extensive group of microRNAs can antagonize TET2. These microRNAs downregulate TET2 and cellular 5-hydroxymethylcytosine, leading to malignant hematopoiesis in vivo. In TET2-wild-type acute myeloid leukemia, TET2-targeting microRNAs are more likely to be overexpressed. These data support the deregulation of TET2-targeting microRNAs as a possible mechanism underlying impaired TET2 function in malignant hematopoiesis.