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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| Vydané v: | Cancer cell Ročník 29; číslo 2; s. 214 |
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| Hlavní autori: | , , , , , , , , , , , , , , , , , , , , , , , , , , , , , |
| Médium: | Journal Article |
| Jazyk: | English |
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United States
08.02.2016
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| ISSN: | 1878-3686, 1878-3686 |
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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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| AbstractList | 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.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. 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. |
| Author | Naldini, Luigi Ciceri, Fabio Ng, Stanley W K Schoof, Erwin M Nilsson, Björn Golub, Todd R Mitchell, Amanda Takayama, Naoya Gentner, Bernhard Hermans, Karin G Nucera, Silvia Lu, Jun Krivdova, Gabriela Dick, John E Marke, Rene van Galen, Peter Wang, Jean C Y Trotman-Grant, Aaron Bader, Gary D Kennedy, James A Lechman, Eric R Kaufmann, Kerstin B Ebert, Benjamin L Zandstra, Peter W Elzinga, Janneke Minden, Mark Dobson, Stephanie M Isserlin, Ruth Eppert, Kolja Voisin, Veronique |
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Department of Molecular Genetics, University of Toronto, Toronto, ON M5G 1L7, Canada – sequence: 5 givenname: Peter surname: van Galen fullname: van Galen, Peter organization: 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 – sequence: 6 givenname: James A surname: Kennedy fullname: Kennedy, James A organization: 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 – sequence: 7 givenname: Silvia surname: Nucera fullname: Nucera, Silvia organization: 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 – sequence: 8 givenname: Fabio surname: Ciceri fullname: Ciceri, Fabio organization: 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 – sequence: 9 givenname: Kerstin B surname: Kaufmann fullname: Kaufmann, Kerstin B organization: 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 – sequence: 10 givenname: Naoya surname: Takayama fullname: Takayama, Naoya organization: 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 – sequence: 11 givenname: Stephanie M surname: Dobson fullname: Dobson, Stephanie M organization: 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 – sequence: 12 givenname: Aaron surname: Trotman-Grant fullname: Trotman-Grant, Aaron organization: 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 – sequence: 13 givenname: Gabriela surname: Krivdova fullname: Krivdova, Gabriela organization: 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 – sequence: 14 givenname: Janneke surname: Elzinga fullname: Elzinga, Janneke organization: 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 – sequence: 15 givenname: Amanda surname: Mitchell fullname: Mitchell, Amanda organization: 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 – sequence: 16 givenname: Björn surname: Nilsson fullname: Nilsson, Björn organization: Department of Hematology and Transfusion Medicine, Lund University Hospital, Lund 221 84, Sweden – sequence: 17 givenname: Karin G surname: Hermans fullname: Hermans, Karin G organization: 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 – sequence: 18 givenname: Kolja surname: Eppert fullname: Eppert, Kolja organization: Department of Pediatrics, McGill University and The Research Institute of the McGill University Health Centre, Montreal, QC H4A 3J1, Canada – sequence: 19 givenname: Rene surname: Marke fullname: Marke, Rene organization: Laboratory of Pediatric Oncology, Radboud University Medical Center, Nijmegen, 6500 HB, Netherlands – sequence: 20 givenname: Ruth surname: Isserlin fullname: Isserlin, Ruth organization: The Donnelly Centre, University of Toronto, Toronto, ON M5S 3E1, Canada – sequence: 21 givenname: Veronique surname: Voisin fullname: Voisin, Veronique organization: The Donnelly Centre, University of Toronto, Toronto, ON M5S 3E1, Canada – sequence: 22 givenname: Gary D surname: Bader fullname: Bader, Gary D organization: The Donnelly Centre, University of Toronto, Toronto, ON M5S 3E1, Canada – sequence: 23 givenname: Peter W surname: Zandstra fullname: Zandstra, Peter W organization: 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 – sequence: 24 givenname: Todd R surname: Golub fullname: Golub, Todd R organization: Department of Pediatric Oncology, Dana-Farber Cancer Institute, 44 Binney Street, Boston, MA 02115, USA – sequence: 25 givenname: Benjamin L surname: Ebert fullname: Ebert, Benjamin L organization: Division of Hematology, Department of Medicine, Brigham and Women's Hospital, Harvard Medical School, Boston, MA 02115, USA – sequence: 26 givenname: Jun surname: Lu fullname: Lu, Jun organization: Yale Stem Cell Center, Yale Cancer Center, Yale University School of Medicine, New Haven, CT 06520, USA – sequence: 27 givenname: Mark surname: Minden fullname: Minden, Mark organization: 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 – sequence: 28 givenname: Jean C Y surname: Wang fullname: Wang, Jean C Y organization: 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 – sequence: 29 givenname: Luigi surname: Naldini fullname: Naldini, Luigi organization: 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 – sequence: 30 givenname: John E surname: Dick fullname: Dick, John E email: jdick@uhnresearch.ca organization: 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 |
| BackLink | https://www.ncbi.nlm.nih.gov/pubmed/26832662$$D View this record in MEDLINE/PubMed |
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| PublicationYear | 2016 |
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| SubjectTerms | 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 |
| Title | miR-126 Regulates Distinct Self-Renewal Outcomes in Normal and Malignant Hematopoietic Stem Cells |
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