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Published March 13, 2012 | Published + Supplemental Material
Journal Article Open

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


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.

Additional Information

© 2012 National Academy of Sciences. Contributed by David Baltimore, January 23, 2012 (sent for review October 29, 2011). We thank Shelley Diamond, Josh Verceles, and Diana Perez of the Caltech Cell Sorting Facility for help in sorting cells. A.A.C. was supported by the Paul and Daisy Soros Fellowship and the National Science Foundation Graduate Research Fellowship Program. A.Y.-L.S. was supported by National Institutes of Health Award 1F32 CA139883-01A1. A. Menta was supported by National Science Foundation Medical Scientist Training Award 5 T32 GM07281. A. Minisandram was supported by a Caltech Summer Undergraduate Research Fellowship. N.S. was supported by the Caltech Amgen Scholars Program. D.S.R. was supported by National Institutes of Health Award 5K08CA133521 and the Sidney Kimmel Foundation. R.M.O. was supported by National Heart, Lung and Blood Institute Award K99HL102228. This work was supported by National Institutes of Health Awards 1R01AI079243 and 1R01AI093531. Author contributions: A.A.C., A.Y.-L.S., R.M.O., and D.B. designed research; A.A.C., A.Y.-L.S., A. Mehta, A. Minisandram, N.S., V.D.J., and D.S.R. performed research; A.A.C., A.Y.-L.S., and R.M.O. contributed new reagents/analytic tools; A.A.C., A.Y.-L.S., V.D.J., D.S.R., and D.B. analyzed data; and A.A.C., A.Y.-L.S., and D.B. wrote the paper. Conflict of interest statement: D.B. is a Director of Regulus, a company devoted to commercialization of antimicro RNA therapies.

Attached Files

Published - Chaudhuri2012p17578P_Natl_Acad_Sci_Usa.pdf

Supplemental Material - pnas.201200677SI.pdf


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