title: The oncogenic microRNA miR-22 targets the TET2 tumor suppressor to promote hematopoietic stem cell self-renewal and transformation.
abstract: MicroRNAs are frequently deregulated in cancer. Here we show that miR-22 is upregulated in myelodysplastic syndrome (MDS) and leukemia and its aberrant expression correlates with poor survival. To explore its role in hematopoietic stem cell function and malignancy, we generated transgenic mice conditionally expressing miR-22 in the hematopoietic compartment. These mice displayed reduced levels of global 5-hydroxymethylcytosine (5-hmC) and increased hematopoietic stem cell self-renewal accompanied by defective differentiation. Conversely, miR-22 inhibition blocked proliferation in both mouse and human leukemic cells. Over time, miR-22 transgenic mice developed MDS and hematological malignancies. We also identify TET2 as a key target of miR-22 in this context. Ectopic expression of TET2 suppressed the miR-22-induced phenotypes. Downregulation of TET2 protein also correlated with poor clinical outcomes and miR-22 overexpression in MDS patients. Our results therefore identify miR-22 as a potent proto-oncogene and suggest that aberrations in the miR-22/TET2 regulatory network are common in hematopoietic malignancies.
authors.affiliation: Cancer Genetics Program, Beth Israel Deaconess Cancer Center, Harvard Medical School, Boston, MA 02215, USA.
authors.forename: Su Jung
authors.initials: SJ
authors.lastname: Song
authors.forename: Keisuke
authors.initials: K
authors.lastname: Ito
authors.forename: Ugo
authors.initials: U
authors.lastname: Ala
authors.forename: Lev
authors.initials: L
authors.lastname: Kats
authors.forename: Kaitlyn
authors.initials: K
authors.lastname: Webster
authors.forename: Su Ming
authors.initials: SM
authors.lastname: Sun
authors.forename: Mojca
authors.initials: M
authors.lastname: Jongen-Lavrencic
authors.forename: Katia
authors.initials: K
authors.lastname: Manova-Todorova
authors.forename: Julie
authors.initials: J
authors.lastname: Teruya-Feldstein
authors.forename: David E
authors.initials: DE
authors.lastname: Avigan
authors.forename: Ruud
authors.initials: R
authors.lastname: Delwel
authors.forename: Pier Paolo
authors.initials: PP
authors.lastname: Pandolfi
mesh_terms: D000818:Animals; D015153:Blotting, Western; D002454:Cell Differentiation; D049109:Cell Proliferation; D002471:Cell Transformation, Neoplastic / Q000235:genetics / Q000378:metabolism / Q000473:pathology*; D004268:DNA-Binding Proteins / Q000235:genetics / Q000378:metabolism*; D049308:Dioxygenases; D005434:Flow Cytometry; D005455:Fluorescent Antibody Technique; D015972:Gene Expression Regulation, Neoplastic; D019337:Hematologic Neoplasms / Q000235:genetics / Q000401:mortality / Q000473:pathology*; D006412:Hematopoietic Stem Cells / Q000166:cytology* / Q000378:metabolism; D006801:Humans; D007124:Immunoenzyme Techniques; D008156:Luciferases / Q000378:metabolism; D051379:Mice; D008810:Mice, Inbred C57BL; D008822:Mice, Transgenic; D035683:MicroRNAs / Q000502:physiology*; D009190:Myelodysplastic Syndromes / Q000235:genetics / Q000401:mortality / Q000473:pathology*; D000090063:Proto-Oncogene Mas; D011518:Proto-Oncogene Proteins / Q000235:genetics / Q000378:metabolism*; D012333:RNA, Messenger / Q000235:genetics; D060888:Real-Time Polymerase Chain Reaction; D020133:Reverse Transcriptase Polymerase Chain Reaction; D015996:Survival Rate
chemical_list: D004268:DNA-Binding Proteins; C000715470:MAS1 protein, human; D035683:MicroRNAs; C574876:Mirn22 microRNA, mouse; D000090063:Proto-Oncogene Mas; D011518:Proto-Oncogene Proteins; D012333:RNA, Messenger; D049308:Dioxygenases; C541081:TET2 protein, human; D008156:Luciferases