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

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

doi:10.1016/j.ccell.2015.12.011

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

Cancer Cell. 2016 Feb 8;29(2):214-28. doi: 10.1016/j.ccell.2015.12.011. Epub 2016 Jan 28.

Authors

Eric R Lechman¹, Bernhard Gentner², Stanley W K Ng³, Erwin M Schoof¹, Peter van Galen¹, James A Kennedy⁴, Silvia Nucera⁵, Fabio Ciceri⁶, Kerstin B Kaufmann¹, Naoya Takayama¹, Stephanie M Dobson¹, Aaron Trotman-Grant¹, Gabriela Krivdova¹, Janneke Elzinga¹, Amanda Mitchell¹, Björn Nilsson⁷, Karin G Hermans¹, Kolja Eppert⁸, Rene Marke⁹, Ruth Isserlin¹⁰, Veronique Voisin¹⁰, Gary D Bader¹⁰, Peter W Zandstra³, Todd R Golub¹¹, Benjamin L Ebert¹², Jun Lu¹³, Mark Minden⁴, Jean C Y Wang⁴, Luigi Naldini⁵, John E Dick¹⁴

Affiliations

¹ 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.
² 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; Hematology and Bone Marrow Transplantation Unit, San Raffaele Hospital, Milan 20132, Italy.
³ 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.
⁴ 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.
⁵ 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.
⁶ 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.
⁷ Department of Hematology and Transfusion Medicine, Lund University Hospital, Lund 221 84, Sweden.
⁸ Department of Pediatrics, McGill University and The Research Institute of the McGill University Health Centre, Montreal, QC H4A 3J1, Canada.
⁹ Laboratory of Pediatric Oncology, Radboud University Medical Center, Nijmegen, 6500 HB, Netherlands.
¹⁰ The Donnelly Centre, University of Toronto, Toronto, ON M5S 3E1, Canada.
¹¹ Department of Pediatric Oncology, Dana-Farber Cancer Institute, 44 Binney Street, Boston, MA 02115, USA.
¹² Division of Hematology, Department of Medicine, Brigham and Women's Hospital, Harvard Medical School, Boston, MA 02115, USA.
¹³ Yale Stem Cell Center, Yale Cancer Center, Yale University School of Medicine, New Haven, CT 06520, USA.
¹⁴ 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: [email protected].

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.

Publication types

Research Support, Non-U.S. Gov't

MeSH terms

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

Substances

Antineoplastic Agents
MIRN126 microRNA, human
MicroRNAs
MTOR protein, human
Proto-Oncogene Proteins c-akt
TOR Serine-Threonine Kinases

Abstract

Publication types

MeSH terms

Substances

Grants and funding