Journal
BLOOD
Volume 125, Issue 8, Pages 1292-1301Publisher
AMER SOC HEMATOLOGY
DOI: 10.1182/blood-2014-06-581892
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Funding
- National Cancer Institute of the National Institutes of Health [U10CA098543, U10CA180886]
- Children with Cancer UK
- Samuel Waxman Cancer Research Foundation NY
- USA Israel Binational Science Foundation
- Israel Science Foundation
- Israel Science Foundation Legacy Heritage program
- Shabbetai Donollo Italian-Israeli Fellowship program
- Kamin program
- Israel Cancer Research Foundation
- Daniel Turnberg UK/Middle East Travel Fellowship from the Academy of Medical Sciences
- National Cancer Institute [CA120772]
- Elana Fund
- Herrick Foundation
- Kids Without Cancer
- Ring Screw Textron Chair for Pediatric Cancer Research
- Leukaemia and Lymphoma Research
- MRC
- BBSRC
- CRUK
- Leukaemia and Lymphoma Society
- NIHR Cambridge Biomedical Research Centre
- Marie Curie Intra-European Fellowship [237296]
- American Society of Hematology Scholar Award
- Alex's Lemonade Stand Foundation Springboard Grant
- BBSRC [BB/I00050X/1] Funding Source: UKRI
- Biotechnology and Biological Sciences Research Council [BB/I00050X/1] Funding Source: researchfish
- Cancer Research UK [12765] Funding Source: researchfish
- Medical Research Council [MC_PC_12009] Funding Source: researchfish
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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 GATA15 isoform. The chromosome 21 microRNA (miR)-125b cluster has been previously shown to cooperate with GATA15 in transformation of fetal hematopoietic progenitors. In this study, we report that the expression of miR-486-5p is increased in ML-DS compared with non-DS acute megakaryocytic leukemias (AMKLs). miR-486-5p is regulated by GATA1 and GATA15 that bind to the promoter of its host gene ANK1. miR-486-5p is highly expressed in mouse erythroid precursors and knockdown (KD) in ML-DS cells reduced their erythroid phenotype. Ectopic expression and KD of miR-486-5p in primary fetal liver hematopoietic progenitors demonstrated that miR-486-5p cooperates with Gatais to enhance their self renewal. Consistent with its activation of AKT, overexpression and KD 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.
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