MicroRNA-486-5p is an oncomiR in the myeloid leukemias of Down Syndrome
Chou, Stella T
Weiss, Mitchell J
Crispino, John D
Taub, Jeffrey W
American Society of Hematology
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Shaham, L., Vendramini, E., Ge, Y., Goren, Y., Birger, Y., Tijssen, M., McNulty, M., et al. (2015). MicroRNA-486-5p is an oncomiR in the myeloid leukemias of Down Syndrome. Blood, 125 1292-1301. https://doi.org/10.1182/blood-2014-06-581892
Children with Down Syndrome (DS) are at increased risk for acute myeloid leukemias (ML-DS) characterized by mixed megakaryocytic and erythroid phenotype and by acquired mutations in the GATA1 gene resulting in a short GATA1s isoform. The chromosome 21 miR-125b cluster has been previously shown to cooperate with GATA1s in transformation of fetal hematopoietic progenitors. Here we report that the expression of miR-486-5p is increased in ML-DS compared to non-DS acute megakaryocytic leukemias (AMKLs). MiR-486-5p is regulated by GATA1 and GATA1s that bind to the promoter of its host gene ANK1. MiR-486-5p is highly expressed in mouse erythroid precursors and knockdown in ML-DS cells reduced their erythroid phenotype. Ectopic expression and knockdown of miR-486-5p in primary fetal liver hematopoietic progenitors demonstrated that miR-486-5p cooperates with Gata1s to enhance their self –renewal. Consistent with its activation of AKT, overexpression and knockdown experiments showed its importance for growth and survival of human leukemic cells. Thus miR-486-5p cooperates with GATA1s in supporting the growth and survival and the aberrant erythroid phenotype of the megakaryocytic leukemias of DS.
Research reported in this publication was supported by the National Cancer Institute of the National Institutes of Health under award number U10CA098543 and U10CA180886. The content is solely the responsibility of the authors and does not necessarily represent the official views of the National Institutes of Health. The study was also supported by Children with Cancer UK (SI), Samuel Waxman Cancer Research Foundation NY and USA Israel Binational Science Foundation (to SI, JC), Israel Science Foundation I-CORE program (SI and SM), Israel Science Foundation Legacy program (SI), The Shabtai Donollo Italian-Israeli Fellowship program (EV), Kamin program (SM), The Israel Cancer Research Foundation and the Daniel Turnberg UK/Middle East Travel Fellowship from the Academy of Medical Sciences (L.G.), The National Cancer Institute (CA120772), Elana Fund, Herrick Foundation, Kids Without Cancer, and the Ring Screw Textron Chair for Pediatric Cancer Research (JT, YG and SI). Research in the Gottgens laboratory is supported by Leukaemia and Lymphoma Research, the MRC, BBSRC, CRUK, Leukaemia and Lymphoma Society, NIHR Cambridge Biomedical Research Centre and core infrastructure support by the Wellcome Trust to the Wellcome Trust and MRC Cambridge Stem Cell Institute and CIMR. M.R.T. was supported by a Marie Curie Intra-European Fellowship (237296). STC was supported by the American Society of Hematology Scholar Award and Alex's Lemonade Stand Foundation Springboard Grant . We acknowledge the Children’s Oncology Group AML Biology Committee for providing patient samples. We thank Ravi Bhatia for miR-486 vectors and for sharing unpublished data.
Leukaemia & Lymphoma Research (12029)
Wellcome Trust (097922/Z/11/Z)
Leukemia & Lymphoma Society (7001-12)
Cancer Research UK (12765)
External DOI: https://doi.org/10.1182/blood-2014-06-581892
This record's URL: https://www.repository.cam.ac.uk/handle/1810/253438