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

Publication date: Available online 28 January 2016
Source:Cancer Cell
Author(s): Eric R. Lechman, Bernhard Gentner, Stanley W.K. Ng, Erwin M. Schoof, Peter van Galen, James A. Kennedy, Silvia Nucera, Fabio Ciceri, Kerstin B. Kaufmann, Naoya Takayama, Stephanie M. Dobson, Aaron Trotman-Grant, Gabriela Krivdova, Janneke Elzinga, Amanda Mitchell, Björn Nilsson, Karin G. Hermans, Kolja Eppert, Rene Marke, Ruth Isserlin, Veronique Voisin, Gary D. Bader, Peter W. Zandstra, Todd R. Golub, Benjamin L. Ebert, Jun Lu, Mark Minden, Jean C.Y. Wang, Luigi Naldini, John E. Dick
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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Teaser

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.

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