title: Runx1 Orchestrates Sphingolipid Metabolism and Glucocorticoid Resistance in Lymphomagenesis.
abstract: The three-membered RUNX gene family includes RUNX1, a major mutational target in human leukemias, and displays hallmarks of both tumor suppressors and oncogenes. In mouse models, the Runx genes appear to act as conditional oncogenes, as ectopic expression is growth suppressive in normal cells but drives lymphoma development potently when combined with over-expressed Myc or loss of p53. Clues to underlying mechanisms emerged previously from murine fibroblasts where ectopic expression of any of the Runx genes promotes survival through direct and indirect regulation of key enzymes in sphingolipid metabolism associated with a shift in the "sphingolipid rheostat" from ceramide to sphingosine-1-phosphate (S1P). Testing of this relationship in lymphoma cells was therefore a high priority. We find that ectopic expression of Runx1 in lymphoma cells consistently perturbs the sphingolipid rheostat, whereas an essential physiological role for Runx1 is revealed by reduced S1P levels in normal spleen after partial Cre-mediated excision. Furthermore, we show that ectopic Runx1 expression confers increased resistance of lymphoma cells to glucocorticoid-mediated apoptosis, and elucidate the mechanism of cross-talk between glucocorticoid and sphingolipid metabolism through Sgpp1. Dexamethasone potently induces expression of Sgpp1 in T-lymphoma cells and drives cell death which is reduced by partial knockdown of Sgpp1 with shRNA or direct transcriptional repression of Sgpp1 by ectopic Runx1. Together these data show that Runx1 plays a role in regulating the sphingolipid rheostat in normal development and that perturbation of this cell fate regulator contributes to Runx-driven lymphomagenesis. J. Cell. Biochem. 118: 1432-1441, 2017. © 2016 Wiley Periodicals, Inc.
authors.affiliation: Molecular Oncology Laboratory, Institute of Infection, Immunity and Inflammation, University of Glasgow, Glasgow, G61 1QH, United Kingdom.
authors.forename: A
authors.initials: A
authors.lastname: Kilbey
authors.affiliation: Molecular Oncology Laboratory, Institute of Infection, Immunity and Inflammation, University of Glasgow, Glasgow, G61 1QH, United Kingdom.
authors.forename: A
authors.initials: A
authors.lastname: Terry
authors.affiliation: Molecular Oncology Laboratory, Institute of Infection, Immunity and Inflammation, University of Glasgow, Glasgow, G61 1QH, United Kingdom.
authors.forename: S
authors.initials: S
authors.lastname: Wotton
authors.affiliation: Molecular Oncology Laboratory, Institute of Infection, Immunity and Inflammation, University of Glasgow, Glasgow, G61 1QH, United Kingdom.
authors.forename: G
authors.initials: G
authors.lastname: Borland
authors.affiliation: The Babraham Institute, Babraham Research Campus, Cambridge, CB22 3AT, Cambridgeshire, United Kingdom.
authors.forename: Q
authors.initials: Q
authors.lastname: Zhang
authors.affiliation: Molecular Oncology Laboratory, Institute of Infection, Immunity and Inflammation, University of Glasgow, Glasgow, G61 1QH, United Kingdom.
authors.forename: N
authors.initials: N
authors.lastname: Mackay
authors.affiliation: Molecular Oncology Laboratory, Institute of Infection, Immunity and Inflammation, University of Glasgow, Glasgow, G61 1QH, United Kingdom.
authors.forename: A
authors.initials: A
authors.lastname: McDonald
authors.affiliation: Molecular Oncology Laboratory, Institute of Infection, Immunity and Inflammation, University of Glasgow, Glasgow, G61 1QH, United Kingdom.
authors.forename: M
authors.initials: M
authors.lastname: Bell
authors.affiliation: The Babraham Institute, Babraham Research Campus, Cambridge, CB22 3AT, Cambridgeshire, United Kingdom.
authors.forename: M J O
authors.initials: MJ
authors.lastname: Wakelam
authors.affiliation: Molecular Oncology Laboratory, Institute of Infection, Immunity and Inflammation, University of Glasgow, Glasgow, G61 1QH, United Kingdom.
authors.forename: E R
authors.initials: ER
authors.lastname: Cameron
authors.affiliation: Molecular Oncology Laboratory, Institute of Infection, Immunity and Inflammation, University of Glasgow, Glasgow, G61 1QH, United Kingdom.
authors.forename: J C
authors.initials: JC
authors.lastname: Neil
mesh_terms: D000818:Animals; D017209:Apoptosis; D045744:Cell Line, Tumor; D050676:Core Binding Factor Alpha 2 Subunit / Q000235:genetics / Q000378:metabolism*; D019008:Drug Resistance, Neoplasm; D015972:Gene Expression Regulation, Neoplastic / Q000187:drug effects; D005938:Glucocorticoids / Q000494:pharmacology*; D008223:Lymphoma / Q000235:genetics* / Q000378:metabolism; D051379:Mice; D009374:Neoplasms, Experimental / Q000235:genetics / Q000378:metabolism; D010744:Phosphoric Monoester Hydrolases / Q000235:genetics*; D043484:Proprotein Convertases / Q000235:genetics; D016271:Proto-Oncogene Proteins c-myc / Q000235:genetics; D012697:Serine Endopeptidases / Q000235:genetics; D013107:Sphingolipids / Q000378:metabolism*; D014158:Transcription, Genetic / Q000187:drug effects; D016159:Tumor Suppressor Protein p53 / Q000235:genetics
chemical_list: D050676:Core Binding Factor Alpha 2 Subunit; D005938:Glucocorticoids; C489428:Myc protein, mouse; D016271:Proto-Oncogene Proteins c-myc; C493726:Runx1 protein, mouse; D013107:Sphingolipids; D016159:Tumor Suppressor Protein p53; C000624969:Sgpp1 protein, mouse; D010744:Phosphoric Monoester Hydrolases; D043484:Proprotein Convertases; D012697:Serine Endopeptidases; C115575:membrane-bound transcription factor peptidase, site 1
keywords: GLUCOCORTICOID; ONCOGENE; Runx1; SPHINGOLIPID; SURVIVAL