TY - JOUR
T1 - The oncogenic MicroRNA miR-22 targets the TET2 tumor suppressor to promote hematopoietic stem cell self-renewal and transformation
AU - Song, Su Jung
AU - Ito, Keisuke
AU - Ala, Ugo
AU - Kats, Lev
AU - Webster, Kaitlyn
AU - Sun, Su Ming
AU - Jongen-Lavrencic, Mojca
AU - Manova-Todorova, Katia
AU - Teruya-Feldstein, Julie
AU - Avigan, David E.
AU - Delwel, Ruud
AU - Pandolfi, Pier Paolo
N1 - Funding Information:
We thank all the members of the Pandolfi laboratory for their comments and discussion. We are grateful to Thomas Garvey and Min Sup Song for critical editing of the manuscript. We are also especially thankful to Akinobu Matsumoto, Dina Stroopinsky, and Mesruh Turkekul for technical support and help on in situ hybridization; to Lourdes Mendez for comments and help on hematological analysis; to Aviv Bergman for comments and support on statistical analysis of human patients’ data; and to Miriam Fayad for support on cohort study of patients with hematological malignancies. K.I. was supported by NIH grants R00CA139009 and R01DK10068901. L.K. was supported by an NHMRC Overseas Biomedical Fellowship. This work was supported by CA141457-03 NIH grants to P.P.P.
PY - 2013/7/3
Y1 - 2013/7/3
N2 - 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-renewalaccompanied by defective differentiation. Conversely, miR- 22 inhibition blocked proliferation in both mouse and human leukemic cells. Over time, miR-22 transgenic mice developedMDSand 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. 2013
AB - 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-renewalaccompanied by defective differentiation. Conversely, miR- 22 inhibition blocked proliferation in both mouse and human leukemic cells. Over time, miR-22 transgenic mice developedMDSand 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. 2013
UR - http://www.scopus.com/inward/record.url?scp=84880571480&partnerID=8YFLogxK
UR - http://www.scopus.com/inward/citedby.url?scp=84880571480&partnerID=8YFLogxK
U2 - 10.1016/j.stem.2013.06.003
DO - 10.1016/j.stem.2013.06.003
M3 - Article
C2 - 23827711
AN - SCOPUS:84880571480
SN - 1934-5909
VL - 13
SP - 87
EP - 101
JO - Cell Stem Cell
JF - Cell Stem Cell
IS - 1
ER -