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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...

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Autores principales: Khalaj, Mona, Woolthuis, Carolien M., Hu, Wenhuo, Durham, Benjamin H., Chu, S. Haihua, Qamar, Sarah, Armstrong, Scott A., Park, Christopher Y.
Formato: Online Artículo Texto
Lenguaje:English
Publicado: The Rockefeller University Press 2017
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.
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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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