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Cancer Cell. 2016 Feb 8;29(2):214-28. doi: 10.1016/j.ccell.2015.12.011. Epub 2016 Jan 28.

miR-126 Regulates Distinct Self-Renewal Outcomes in Normal and Malignant Hematopoietic Stem Cells.

Author information

1
Princess Margaret Cancer Centre, University Health Network, University of Toronto, Toronto, ON M5G 1L7, Canada; Department of Molecular Genetics, University of Toronto, Toronto, ON M5G 1L7, Canada.
2
San Raffaele Telethon Institute for Gene Therapy, San Raffaele Hospital, Milan 20132, Italy; Vita Salute San Raffaele University, San Raffaele Scientific Institute, San Raffaele Hospital, Milan 20132, Italy; Hematology and Bone Marrow Transplantation Unit, San Raffaele Hospital, Milan 20132, Italy.
3
Department of Chemical Engineering and Applied Chemistry, Institute of Biomaterials and Biomedical Engineering, University of Toronto, Toronto, ON M5G 2M9, Canada; The Donnelly Centre, University of Toronto, Toronto, ON M5S 3E1, Canada.
4
Princess Margaret Cancer Centre, University Health Network, University of Toronto, Toronto, ON M5G 1L7, Canada; Department of Medicine, University of Toronto, Toronto, ON M5G 2M9, Canada.
5
San Raffaele Telethon Institute for Gene Therapy, San Raffaele Hospital, Milan 20132, Italy; Vita Salute San Raffaele University, San Raffaele Scientific Institute, San Raffaele Hospital, Milan 20132, Italy.
6
Vita Salute San Raffaele University, San Raffaele Scientific Institute, San Raffaele Hospital, Milan 20132, Italy; Hematology and Bone Marrow Transplantation Unit, San Raffaele Hospital, Milan 20132, Italy.
7
Department of Hematology and Transfusion Medicine, Lund University Hospital, Lund 221 84, Sweden.
8
Department of Pediatrics, McGill University and The Research Institute of the McGill University Health Centre, Montreal, QC H4A 3J1, Canada.
9
Laboratory of Pediatric Oncology, Radboud University Medical Center, Nijmegen, 6500 HB, Netherlands.
10
The Donnelly Centre, University of Toronto, Toronto, ON M5S 3E1, Canada.
11
Department of Pediatric Oncology, Dana-Farber Cancer Institute, 44 Binney Street, Boston, MA 02115, USA.
12
Division of Hematology, Department of Medicine, Brigham and Women's Hospital, Harvard Medical School, Boston, MA 02115, USA.
13
Yale Stem Cell Center, Yale Cancer Center, Yale University School of Medicine, New Haven, CT 06520, USA.
14
Princess Margaret Cancer Centre, University Health Network, University of Toronto, Toronto, ON M5G 1L7, Canada; Department of Molecular Genetics, University of Toronto, Toronto, ON M5G 1L7, Canada; Princess Margaret Cancer Research Tower, Room 8-301, 101 College Street, Toronto M5G 1L7, Canada. Electronic address: jdick@uhnresearch.ca.

Abstract

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.

PMID:
26832662
PMCID:
PMC4749543
DOI:
10.1016/j.ccell.2015.12.011
[Indexed for MEDLINE]
Free PMC Article
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