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

Eric R. Lechman(University Health Network), Bernhard Gentner(Vita-Salute San Raffaele University), Stanley W.K. Ng(University of Toronto), Erwin M. Schoof(University Health Network), Peter van Galen(Princess Margaret Cancer Centre), Theodore A. Kennedy(University of Toronto), Silvia Nucera(The San Raffaele Telethon Institute for Gene Therapy), Fabio Ciceri(Vita-Salute San Raffaele University), Kerstin B. Kaufmann(University Health Network), Naoya Takayama(University of Toronto), Stephanie M. Dobson(Princess Margaret Cancer Centre), Aaron C. Trotman-Grant(Princess Margaret Cancer Centre), Gabriela Krivdova(University of Toronto), Janneke Elzinga(Princess Margaret Cancer Centre), Amanda Mitchell(University Health Network), Björn Nilsson(Lund University), Karin G. Hermans(University Health Network), Kolja Eppert(McGill University Health Centre), René Marke(Radboud University Medical Center), Ruth Isserlin(University of Toronto), Véronique Voisin(University of Toronto), Gary D. Bader(University of Toronto), Peter W. Zandstra(University of Toronto), Todd R. Golub(Dana-Farber Cancer Institute), Benjamin L. Ebert(Brigham and Women's Hospital), Jun Lü(Yale Cancer Center), Mark D. Minden(University of Toronto), Jean Wang(Princess Margaret Cancer Centre), Luigi Naldini(Vita-Salute San Raffaele University), John E. Dick(University Health Network)
Cancer Cell
January 28, 2016
10.1016/j.ccell.2015.12.011
Cited by 265Open Access
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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.

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