MicroRNAs enriched in hematopoietic stem cells differentially regulate long-term hematopoietic output
Abstract
The production of blood cells depends on a rare hematopoietic stem-cell (HSC) population, but the molecular mechanisms underlying HSC biology remain incompletely understood. Here, we identify a subset of microRNAs (miRNAs) that is enriched in HSCs compared with other bone-marrow cells. An in vivo gain-of-function screen found that three of these miRNAs conferred a competitive advantage to engrafting hematopoietic cells, whereas other HSC miRNAs attenuated production of blood cells. Overexpression of the most advantageous miRNA, miR-125b, caused a dose-dependent myeloproliferative disorder that progressed to a lethal myeloid leukemia in mice and also enhanced hematopoietic engraftment in human immune system mice. Our study identifies an evolutionarily conserved subset of miRNAs that is expressed in HSCs and functions to modulate hematopoietic output.
Additional Information
© 2010 by the National Academy of Sciences. Contributed by David Baltimore, July 7, 2010 (sent for review June 25, 2010). We thank the Caltech FACS core facility for their assistance with cell sorting. R.M.O. was funded in part by the Irvington Institute Fellowship Program of the Cancer Research Institute and by Award K99HL102228 from the National Heart, Lung, and Blood Institute. A.A.C. was funded by the Graduate Research Fellowship Program of the National Science Foundation. D.S.R. was funded by Award 1K08CA133521 from the National Cancer Institute. A.B.B. is supported by American Foundation for AIDS Research (amfAR) fellowship #107756-47-RFVA. This work was also supported by National Institutes of Health Grant 1R01AI079243-01. Author contributions: R.M.O., A.A.C., D.S.R., W.S.J.G., A.B.B., and D.B. designed research; R.M.O., A.A.C., D.S.R., and W.S.J.G. performed research; R.M.O. and A.A.C. contributed new reagents/analytic tools; R.M.O., A.A.C., D.S.R., W.S.J.G., A.B.B., and D.B. analyzed data; and R.M.O., A.A.C., and D.B. wrote the paper. Conflict of interest statement: The authors declare that they have no competing financial interests except for D.B., who is a scientific advisor to Regulus Therapeutics, a company devoted to microRNA therapeutics. R.M.O and A.A.C. contributed equally to this work.Attached Files
Published - OConnell2010p11312P_Natl_Acad_Sci_Usa.pdf
Supplemental Material - pnas.201009798SI.pdf
Supplemental Material - st01.doc
Supplemental Material - st02.doc
Files
Additional details
- PMCID
- PMC2922591
- Eprint ID
- 19908
- Resolver ID
- CaltechAUTHORS:20100913-113144776
- Cancer Research Institute
- K99HL102228
- NIH
- NSF
- 1K08CA133521
- NIH
- 107756-47-RFVA
- American Foundation for AIDS Research (amfAR)
- 1R01AI079243-01
- NIH
- National Heart, Lung, and Blood Institute
- National Cancer Institute
- Created
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2010-09-15Created from EPrint's datestamp field
- Updated
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2021-11-08Created from EPrint's last_modified field