title: Addiction to Runx1 is partially attenuated by loss of p53 in the Eµ-Myc lymphoma model.
abstract: The Runx genes function as dominant oncogenes that collaborate potently with Myc or loss of p53 to induce lymphoma when over-expressed. Here we examined the requirement for basal Runx1 activity for tumor maintenance in the Eµ-Myc model of Burkitt's lymphoma. While normal Runx1fl/fl lymphoid cells permit mono-allelic deletion, primary Eµ-Myc lymphomas showed selection for retention of both alleles and attempts to enforce deletion in vivo led to compensatory expansion of p53null blasts retaining Runx1. Surprisingly, Runx1 could be excised completely from established Eµ-Myc lymphoma cell lines in vitro without obvious effects on cell phenotype. Established lines lacked functional p53, and were sensitive to death induced by introduction of a temperature-sensitive p53 (Val135) allele. Transcriptome analysis of Runx1-deleted cells revealed a gene signature associated with lymphoid proliferation, survival and differentiation, and included strong de-repression of recombination-activating (Rag) genes, an observation that was mirrored in a panel of human acute leukemias where RUNX1 and RAG1,2 mRNA expression were negatively correlated. Notably, despite their continued growth and tumorigenic potential, Runx1null lymphoma cells displayed impaired proliferation and markedly increased sensitivity to DNA damage and dexamethasone-induced apoptosis, validating Runx1 function as a potential therapeutic target in Myc-driven lymphomas regardless of their p53 status.
authors.affiliation: Molecular Oncology Laboratory, Institute of Infection, Immunity and Inflammation, University of Glasgow, Glasgow, UK.
authors.forename: Gillian
authors.initials: G
authors.lastname: Borland
authors.affiliation: Molecular Oncology Laboratory, Institute of Infection, Immunity and Inflammation, University of Glasgow, Glasgow, UK.
authors.forename: Anna
authors.initials: A
authors.lastname: Kilbey
authors.affiliation: Molecular Oncology Laboratory, Institute of Infection, Immunity and Inflammation, University of Glasgow, Glasgow, UK.
authors.forename: Jodie
authors.initials: J
authors.lastname: Hay
authors.affiliation: Molecular Oncology Laboratory, Institute of Infection, Immunity and Inflammation, University of Glasgow, Glasgow, UK.
authors.forename: Kathryn
authors.initials: K
authors.lastname: Gilroy
authors.affiliation: Molecular Oncology Laboratory, Institute of Infection, Immunity and Inflammation, University of Glasgow, Glasgow, UK.
authors.forename: Anne
authors.initials: A
authors.lastname: Terry
authors.affiliation: Molecular Oncology Laboratory, Institute of Infection, Immunity and Inflammation, University of Glasgow, Glasgow, UK.
authors.forename: Nancy
authors.initials: N
authors.lastname: Mackay
authors.affiliation: School of Veterinary Medicine, University of Glasgow, Glasgow, UK.
authors.forename: Margaret
authors.initials: M
authors.lastname: Bell
authors.affiliation: Molecular Oncology Laboratory, Institute of Infection, Immunity and Inflammation, University of Glasgow, Glasgow, UK.
authors.forename: Alma
authors.initials: A
authors.lastname: McDonald
authors.affiliation: Centre for Cancer Research and Cell Biology, Queen's University Belfast, Belfast, UK.
authors.forename: Ken
authors.initials: K
authors.lastname: Mills
authors.affiliation: School of Veterinary Medicine, University of Glasgow, Glasgow, UK.
authors.forename: Ewan
authors.initials: E
authors.lastname: Cameron
authors.affiliation: Molecular Oncology Laboratory, Institute of Infection, Immunity and Inflammation, University of Glasgow, Glasgow, UK.
authors.forename: James C
authors.initials: JC
authors.lastname: Neil
mesh_terms: D000818:Animals; D017209:Apoptosis; D049109:Cell Proliferation; D050676:Core Binding Factor Alpha 2 Subunit / Q000235:genetics / Q000378:metabolism*; D004195:Disease Models, Animal; D005260:Female; D006801:Humans; D008223:Lymphoma / Q000235:genetics / Q000378:metabolism / Q000473:pathology*; D008297:Male; D051379:Mice; D016688:Mice, Inbred NOD; D016513:Mice, SCID; D008822:Mice, Transgenic; D016271:Proto-Oncogene Proteins c-myc / Q000502:physiology*; D014407:Tumor Cells, Cultured; D016159:Tumor Suppressor Protein p53 / Q000502:physiology*
chemical_list: D050676:Core Binding Factor Alpha 2 Subunit; D016271:Proto-Oncogene Proteins c-myc; D016159:Tumor Suppressor Protein p53
keywords: Runx1; lymphoma; myc; oncogene addiction