Journal Article

Oncomir miR-125b regulates hematopoiesis by targeting the gene Lin28A

Jonsson, Vanessa D, Sinha, Nikita, Baltimore, David, O'Connell, Ryan M, Mehta, Arnav, Rao, Dinesh S, Chaudhuri, Aadel A, So, Alex Yick-Lun, Minisandram, Aarathi

2012

Overview

MicroRNA-125b (miR-125b) is up-regulated in patients with leukemia. Overexpression of miR-125b alone in mice causes a very aggressive, transplantable myeloid leukemia. Before leukemia, these mice do not display elevation of white blood cells in the spleen or bone marrow; rather, the hematopoietic compartment shows lineage-skewing, with myeloid cell numbers dramatically increased and B-cell numbers severely diminished. miR-125b exerts this effect by up-regulating the number of common myeloid progenitors while inhibiting development of pre-B cells. We applied a miR-125b sponge loss of function system in vivo to show that miR-125b physiologically regulates hematopoietic development. Investigating the mechanism by which miR-125b regulates hematopoiesis, we found that, among a panel of candidate targets, the mRNA for Lin28A, an induced pluripotent stem cell gene, was most repressed by miR-125b in mouse hematopoietic stem and progenitor cells. Overexpressing Lin28A in the mouse hematopoietic system mimicked the phenotype observed on inhibiting miR-125b function, leading to a decrease in hematopoietic output. Relevant to the miR-125b overexpression phenotype, we also found that knockdown of Lin28A led to hematopoietic lineage-skewing, with increased myeloid and decreased B-cell numbers. Thus, the miR-125b target Lin28A is an important regulator of hematopoiesis and a primary target of miR-125b in the hematopoietic system.

• Publisher: National Academy of Sciences,National Acad Sciences
• Subject: Animals / B-lymphocytes / B-Lymphocytes - metabolism / B-Lymphocytes - pathology / Biological Sciences / Bone marrow / Bone Marrow - metabolism / Bone Marrow - pathology / Cancer / Cell Count / Cell Differentiation / Cell Differentiation - genetics / Cells / Gene expression regulation / Gene Expression Regulation, Leukemic / gene overexpression / gene targeting / genes / genetics / Genotype & phenotype / Hematopoiesis / Hematopoiesis - genetics / Hematopoietic stem cells / Hemopoiesis / Humans / K562 cells / Leukemia / Leukemia, Myeloid / Leukemia, Myeloid - genetics / Leukemia, Myeloid - pathology / Leukocytes / Lymphocytes B / messenger RNA / metabolism / Mice / Mice, Inbred C57BL / MicroRNAs / MicroRNAs - genetics / MicroRNAs - metabolism / miRNA / Myeloid Cells / Myeloid Cells - metabolism / Myeloid Cells - pathology / Myeloid leukemia / Neoplasm Invasiveness / pathology / patients / phenotype / Pluripotent stem cells / RNA-Binding Proteins / RNA-Binding Proteins - genetics / RNA-Binding Proteins - metabolism / Rodents / Spleen / splenocytes / Stem cells