miR-99 regulates normal and malignant hematopoietic stem cell self-renewal

Mona Khalaj, Carolien M. Woolthuis, Wenhuo Hu, Benjamin H. Durham, S. Haihua Chu, Sarah Qamar, Scott A. Armstrong, Christopher Y. Park*

*Bijbehorende auteur voor dit werk

OnderzoeksoutputAcademicpeer review

16 Citaten (Scopus)
140 Downloads (Pure)

Samenvatting

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.

Originele taal-2English
Pagina's (van-tot)2453-2470
Aantal pagina's18
TijdschriftJournal of Experimental Medicine
Volume214
Nummer van het tijdschrift8
DOI's
StatusPublished - aug-2017
Extern gepubliceerdJa

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