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

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 L...

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Published in:Cancer cell Vol. 29; no. 2; p. 214
Main Authors: Lechman, Eric R, Gentner, Bernhard, Ng, Stanley W K, Schoof, Erwin M, van Galen, Peter, Kennedy, James A, Nucera, Silvia, Ciceri, Fabio, Kaufmann, Kerstin B, Takayama, Naoya, Dobson, Stephanie M, Trotman-Grant, Aaron, Krivdova, Gabriela, Elzinga, Janneke, Mitchell, Amanda, Nilsson, Björn, Hermans, Karin G, Eppert, Kolja, Marke, Rene, Isserlin, Ruth, Voisin, Veronique, Bader, Gary D, Zandstra, Peter W, Golub, Todd R, Ebert, Benjamin L, Lu, Jun, Minden, Mark, Wang, Jean C Y, Naldini, Luigi, Dick, John E
Format: Journal Article
Language:English
Published: United States 08.02.2016
Subjects:
Animals
Antineoplastic Agents - pharmacology
Cell Line, Tumor
Gene Knockdown Techniques
Hematopoietic Stem Cells - pathology
Heterografts
Humans
Leukemia, Myeloid, Acute - genetics
Leukemia, Myeloid, Acute - pathology
Mice
Mice, SCID
MicroRNAs - genetics
MicroRNAs - physiology
Phosphatidylinositol 3-Kinases - metabolism
Prognosis
Proto-Oncogene Proteins c-akt - metabolism
TOR Serine-Threonine Kinases - metabolism
ISSN:1878-3686, 1878-3686
Online Access:Get more information
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Summary: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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ISSN:1878-3686
1878-3686
DOI:10.1016/j.ccell.2015.12.011