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miR-99 regulates normal and malignant hematopoietic stem cell self-renewal
The microRNA-99 (miR-99) family comprises a group of broadly conserved microRNAs that are highly expressed in hematopoietic stem cells (HSCs) and acute myeloid leukemia stem cells (LSCs) compared with their differentiated progeny. Herein, we show that miR-99 regulates self-renewal in both HSCs and L...
Autores principales: | , , , , , , , |
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Formato: | Online Artículo Texto |
Lenguaje: | English |
Publicado: |
The Rockefeller University Press
2017
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Materias: | |
Acceso en línea: | https://www.ncbi.nlm.nih.gov/pmc/articles/PMC5551568/ https://www.ncbi.nlm.nih.gov/pubmed/28733386 http://dx.doi.org/10.1084/jem.20161595 |
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author | Khalaj, Mona Woolthuis, Carolien M. Hu, Wenhuo Durham, Benjamin H. Chu, S. Haihua Qamar, Sarah Armstrong, Scott A. Park, Christopher Y. |
author_facet | Khalaj, Mona Woolthuis, Carolien M. Hu, Wenhuo Durham, Benjamin H. Chu, S. Haihua Qamar, Sarah Armstrong, Scott A. Park, Christopher Y. |
author_sort | Khalaj, Mona |
collection | PubMed |
description | The microRNA-99 (miR-99) family comprises a group of broadly conserved microRNAs that are highly expressed in hematopoietic stem cells (HSCs) and acute myeloid leukemia stem cells (LSCs) compared with their differentiated progeny. Herein, we show that miR-99 regulates self-renewal in both HSCs and LSCs. miR-99 maintains HSC long-term reconstitution activity by inhibiting differentiation and cell cycle entry. Moreover, miR-99 inhibition induced LSC differentiation and depletion in an MLL-AF9–driven mouse model of AML, leading to reduction in leukemia-initiating activity and improved survival in secondary transplants. Confirming miR-99’s role in established AML, miR-99 inhibition induced primary AML patient blasts to undergo differentiation. A forward genetic shRNA library screen revealed Hoxa1 as a critical mediator of miR-99 function in HSC maintenance, and this observation was independently confirmed in both HSCs and LSCs. Together, these studies demonstrate the importance of noncoding RNAs in the regulation of HSC and LSC function and identify miR-99 as a critical regulator of stem cell self-renewal. |
format | Online Article Text |
id | pubmed-5551568 |
institution | National Center for Biotechnology Information |
language | English |
publishDate | 2017 |
publisher | The Rockefeller University Press |
record_format | MEDLINE/PubMed |
spelling | pubmed-55515682018-02-07 miR-99 regulates normal and malignant hematopoietic stem cell self-renewal Khalaj, Mona Woolthuis, Carolien M. Hu, Wenhuo Durham, Benjamin H. Chu, S. Haihua Qamar, Sarah Armstrong, Scott A. Park, Christopher Y. J Exp Med Research Articles The microRNA-99 (miR-99) family comprises a group of broadly conserved microRNAs that are highly expressed in hematopoietic stem cells (HSCs) and acute myeloid leukemia stem cells (LSCs) compared with their differentiated progeny. Herein, we show that miR-99 regulates self-renewal in both HSCs and LSCs. miR-99 maintains HSC long-term reconstitution activity by inhibiting differentiation and cell cycle entry. Moreover, miR-99 inhibition induced LSC differentiation and depletion in an MLL-AF9–driven mouse model of AML, leading to reduction in leukemia-initiating activity and improved survival in secondary transplants. Confirming miR-99’s role in established AML, miR-99 inhibition induced primary AML patient blasts to undergo differentiation. A forward genetic shRNA library screen revealed Hoxa1 as a critical mediator of miR-99 function in HSC maintenance, and this observation was independently confirmed in both HSCs and LSCs. Together, these studies demonstrate the importance of noncoding RNAs in the regulation of HSC and LSC function and identify miR-99 as a critical regulator of stem cell self-renewal. The Rockefeller University Press 2017-08-07 /pmc/articles/PMC5551568/ /pubmed/28733386 http://dx.doi.org/10.1084/jem.20161595 Text en © 2017 Khalaj et al. http://www.rupress.org/terms/https://creativecommons.org/licenses/by-nc-sa/4.0/This article is distributed under the terms of an Attribution–Noncommercial–Share Alike–No Mirror Sites license for the first six months after the publication date (see http://www.rupress.org/terms/). After six months it is available under a Creative Commons License (Attribution–Noncommercial–Share Alike 4.0 International license, as described at https://creativecommons.org/licenses/by-nc-sa/4.0/). |
spellingShingle | Research Articles Khalaj, Mona Woolthuis, Carolien M. Hu, Wenhuo Durham, Benjamin H. Chu, S. Haihua Qamar, Sarah Armstrong, Scott A. Park, Christopher Y. miR-99 regulates normal and malignant hematopoietic stem cell self-renewal |
title | miR-99 regulates normal and malignant hematopoietic stem cell self-renewal |
title_full | miR-99 regulates normal and malignant hematopoietic stem cell self-renewal |
title_fullStr | miR-99 regulates normal and malignant hematopoietic stem cell self-renewal |
title_full_unstemmed | miR-99 regulates normal and malignant hematopoietic stem cell self-renewal |
title_short | miR-99 regulates normal and malignant hematopoietic stem cell self-renewal |
title_sort | mir-99 regulates normal and malignant hematopoietic stem cell self-renewal |
topic | Research Articles |
url | https://www.ncbi.nlm.nih.gov/pmc/articles/PMC5551568/ https://www.ncbi.nlm.nih.gov/pubmed/28733386 http://dx.doi.org/10.1084/jem.20161595 |
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