The Oncogenic MicroRNA miR-22 Targets the TET2 Tumor Suppressor to Promote Hematopoietic Stem Cell Self-Renewal and Transformation
Menée à l'aide d'un modèle murin, cette étude met en évidence des mécanismes par lesquels, en ciblant le gène TET2, le micro-ARN 22 favorise le développement d'une leucémie
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. "miR-22-TET2 regulatory network controls hematopoietic stem cell biology "miR-22 triggers myelodysplastic syndrome and hematological malignancies "Levels of miR-22 and TET2 are reliable prognostic factors in MDS patients The microRNA miR-22 participates in the initiation of leukemia by targeting TET2 and high expression correlates with poor clinical outcomes, making it an attractive therapeutic target.
http://linkinghub.elsevier.com/retrieve/pii/S1934590913002610