title: INK4a/ARF mutations accelerate lymphomagenesis and promote chemoresistance by disabling p53.
abstract: The INK4a/ARF locus encodes upstream regulators of the retinoblastoma and p53 tumor suppressor gene products. To compare the impact of these loci on tumor development and treatment response, the Emu-myc transgenic lymphoma model was used to generate genetically defined tumors with mutations in the INK4a/ARF, Rb, or p53 genes. Like p53 null lymphomas, INK4a/ARF null lymphomas formed rapidly, were highly invasive, displayed apoptotic defects, and were markedly resistant to chemotherapy in vitro and in vivo. Furthermore, INK4a/ARF(-/-) lymphomas displayed reduced p53 activity despite the presence of wild-type p53 genes. Consequently, INK4a/ARF and p53 mutations lead to aggressive tumors by disrupting overlapping tumor suppressor functions. These data have important implications for understanding the clinical behavior of human tumors.
authors.affiliation: Cold Spring Harbor Laboratory, Cold Spring Harbor, New York 11724, USA.
authors.forename: C A
authors.initials: CA
authors.lastname: Schmitt
authors.forename: M E
authors.initials: ME
authors.lastname: McCurrach
authors.forename: E
authors.initials: E
authors.lastname: de Stanchina
authors.forename: R R
authors.initials: RR
authors.lastname: Wallace-Brodeur
authors.forename: S W
authors.initials: SW
authors.lastname: Lowe
mesh_terms: D000818:Animals; D000970:Antineoplastic Agents / Q000494:pharmacology; D017209:Apoptosis / Q000235:genetics; D004351:Drug Resistance / Q000235:genetics; D004742:Enhancer Elements, Genetic; D005260:Female; D016259:Genes, myc; D019942:Genes, p16; D016158:Genes, p53; D006801:Humans; D007143:Immunoglobulin Heavy Chains / Q000235:genetics; D016393:Lymphoma, B-Cell / Q000188:drug therapy / Q000209:etiology* / Q000235:genetics*; D008297:Male; D051379:Mice; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D008822:Mice, Transgenic; D009154:Mutation; D011506:Proteins / Q000235:genetics*; D025803:Tumor Suppressor Protein p14ARF
chemical_list: D000970:Antineoplastic Agents; D007143:Immunoglobulin Heavy Chains; D011506:Proteins; D025803:Tumor Suppressor Protein p14ARF