MicroRNAs enriched in hematopoietic stem cells differentially regulate long-term hematopoietic output

Ryan M. O'Connell; Aadel A. Chaudhuri; Dinesh S. Rao; William S.J. Gibson; Alejandro B. Balazs; David Baltimore

doi:10.1073/pnas.1009798107

MicroRNAs enriched in hematopoietic stem cells differentially regulate long-term hematopoietic output

Ryan M. O'Connell, Aadel A. Chaudhuri, Dinesh S. Rao, William S.J. Gibson, Alejandro B. Balazs, David Baltimore

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229 Scopus citations

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.

Original language	English
Pages (from-to)	14235-14240
Number of pages	6
Journal	Proceedings of the National Academy of Sciences of the United States of America
Volume	107
Issue number	32
DOIs	https://doi.org/10.1073/pnas.1009798107
State	Published - Aug 10 2010

Keywords

Cancer
Inflammation
Myeloid
Noncoding RNA
Xenograft

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title = "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.",

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AU - O'Connell, Ryan M.

AU - Chaudhuri, Aadel A.

AU - Rao, Dinesh S.

AU - Gibson, William S.J.

AU - Balazs, Alejandro B.

AU - Baltimore, David

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N2 - 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.

AB - 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.

KW - Cancer

KW - Inflammation

KW - Myeloid

KW - Noncoding RNA

KW - Xenograft

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MicroRNAs enriched in hematopoietic stem cells differentially regulate long-term hematopoietic output

Abstract

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