한빛사논문
Abstract
Su Jung Song1, 2, 3, 4, 9, Keisuke Ito1, 2, 3, 4, 9, 10, Ugo Ala1, 2, 3, 4, Lev Kats1, 2, 3, 4, Kaitlyn Webster1, 2, 3, 4, Su Ming Sun6, Mojca Jongen-Lavrencic6, Katia Manova-Todorova7, Julie Teruya-Feldstein8, David E. Avigan5, Ruud Delwel6, Pier Paolo Pandolfi1, 2, 3, 4,*
1 Cancer Genetics Program, Beth Israel Deaconess Cancer Center, Harvard Medical School, Boston, MA 02215, USA
2 Department of Medicine, Division of Genetics, Beth Israel Deaconess Medical Center, Harvard Medical School, Boston, MA 02215, USA
3 Department of Pathology, Beth Israel Deaconess Medical Center, Harvard Medical School, Boston, MA 02215, USA
4 Division of Genetics, Beth Israel Deaconess Medical Center, Harvard Medical School, Boston, MA 02215, USA
5 Division of Hematology and Oncology, Beth Israel Deaconess Medical Center, Harvard Medical School, Boston, MA 02215, USA
6 The Institute for Hematology, Erasmus Medical Center, Rotterdam 5201, Netherlands
7 Molecular Cytology, Sloan-Kettering Institute, Memorial Sloan-Kettering Cancer Center, New York, NY 10065, USA
8 Department of Pathology, Sloan-Kettering Institute, Memorial Sloan-Kettering Cancer Center, New York, NY 10065, USA
9These authors contributed equally to this work
10Present address: Ruth L. and David S. Gottesman Institute for Stem Cell and Regenerative Medicine Research, Departments of Cell Biology/Stem Cell Institute and Medicine, Albert Einstein Cancer Center, Albert Einstein College of Medicine, Bronx, NY 10461, USA
*Corresponding author
Summary
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.
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