MiR-126 Regulates Distinct Self-Renewal Outcomes in Normal and Malignant Hematopoietic Stem Cells
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To investigate miRNA function in human acute myeloid leukemia (AML) stem cells (LSC), we generated a prognostic LSC-associated miRNA signature derived from functionally validated subpopulations of AML samples. For one signature miRNA, miR-126, high bioactivity aggregated all in vivo patient sample LSC activity into a single sorted population, tightly coupling miR-126 expression to LSC function. Through functional studies, miR-126 was found to restrain cell cycle progression, prevent differentiation, and increase self-renewal of primary LSC in vivo. Compared with prior results showing miR-126 regulation of normal hematopoietic stem cell (HSC) cycling, these functional stem effects are opposite between LSC and HSC. Combined transcriptome and proteome analysis demonstrates that miR-126 targets the PI3K/AKT/MTOR signaling pathway, preserving LSC quiescence and promoting chemotherapy resistance. Lechman et al. show that miR-126 targets the PI3K/AKT/MTOR signaling pathway to preserve quiescence, increase self-renewal, and promote chemotherapy resistance of acute myeloid leukemia stem cells (LSC). Reducing the miR-126 level impairs LSC maintenance in contrast to expanding normal hematopoietic stem cells.
Original language | English |
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Journal | Cancer Cell |
Volume | 29 |
Issue number | 2 |
Pages (from-to) | 214-228 |
Number of pages | 15 |
ISSN | 1535-6108 |
DOIs | |
Publication status | Published - 8 Feb 2016 |
Bibliographical note
Funding Information:
We thank Dr. M Roehrl for mass spectrometer support, A Khandani and P. A. Penttilä for flow cytometry, and the Dick and Naldini laboratories for critical review. This work was supported by grants to L.N. from Telethon (TIGET grant), EU ( FP7 GA 222878 PERSIST, ERC Advanced Grant 249845 TARGETING GENE THERAPY), and the Italian Ministry of Health and to J.E.D. from the Canadian Institutes for Health Research , Canadian Cancer Society , Terry Fox Foundation , Genome Canada through the Ontario Genomics Institute , Ontario Institute for Cancer Research with funds from the Province of Ontario , and a Canada Research Chair . E.M.S. is an EMBO Postdoctoral Fellow (ALTF 1595–2014) and is co-funded by the European Commission (LTFCOFUND2013, GA-2013-609409 ) and Marie Curie Actions . This research was funded in part by the Ontario Ministry of Health and Long Term Care (OMOHLTC). The views expressed do not necessarily reflect those of the OMOHLTC.
Publisher Copyright:
© 2016 The Authors.
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