miR-126 Regulates Distinct Self-Renewal Outcomes in Normal and Malignant Hematopoietic Stem Cells
| Autor: | Fabio Ciceri, Mark D. Minden, Björn Nilsson, Veronique Voisin, Peter W. Zandstra, Stephanie M. Dobson, Benjamin L. Ebert, Ruth Isserlin, Todd R. Golub, Kerstin B. Kaufmann, Bernhard Gentner, Rene Marke, John E. Dick, Erwin M. Schoof, Amanda Mitchell, Stanley W.K. Ng, Luigi Naldini, Kolja Eppert, Eric R. Lechman, James A. Kennedy, Karin G. Hermans, Naoya Takayama, Jean C.Y. Wang, Jun Lu, Aaron Trotman-Grant, Silvia Nucera, Janneke Elzinga, Gary D. Bader, Gabriela Krivdova, Peter van Galen |
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| Přispěvatelé: | Lechman, E. R., Gentner, B., Ng, S. W. K., Schoof, E. M., van Galen, P., Kennedy, J. A., Nucera, S., Ciceri, F., Kaufmann, K. B., Takayama, N., Dobson, S. M., Trotman-Grant, A., Krivdova, G., Elzinga, J., Mitchell, A., Nilsson, B., Hermans, K. G., Eppert, K., Marke, R., Isserlin, R., Voisin, V., Bader, G. D., Zandstra, P. W., Golub, T. R., Ebert, B. L., Lu, J., Minden, M., Wang, J. C. Y., Naldini, L., Dick, J. E. |
| Rok vydání: | 2014 |
| Předmět: |
0301 basic medicine
Cancer Research Population Antineoplastic Agents Mice SCID Self renewal Biology Article Transcriptome 03 medical and health sciences Mice Phosphatidylinositol 3-Kinases 0302 clinical medicine Cell Line Tumor microRNA medicine Animals Humans education PI3K/AKT/mTOR pathway education.field_of_study TOR Serine-Threonine Kinases Hematopoietic stem cell Myeloid leukemia Cell Biology Hematopoietic Stem Cells Prognosis 3. Good health Haematopoiesis Leukemia Myeloid Acute MicroRNAs medicine.anatomical_structure 030104 developmental biology Oncology 030220 oncology & carcinogenesis Gene Knockdown Techniques Immunology Cancer research Heterografts sense organs Stem cell Proto-Oncogene Proteins c-akt |
| Zdroj: | Transl Cancer Res Cancer Cell |
| ISSN: | 1878-3686 |
| Popis: | 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. |
| Databáze: | OpenAIRE |
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