MicroRNA 486 5p is an oncomiR in the myeloid leukemias of Down Syndrome

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.