INK4a/ARF mutations accelerate lymphomagenesis and promote chemoresistance by disabling p53.
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.
Schmitt
C A
CA
Cold Spring Harbor Laboratory, Cold Spring Harbor, New York 11724, USA.
McCurrach
M E
ME
de Stanchina
E
E
Wallace-Brodeur
R R
RR
Lowe
S W
SW
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
D000970:Antineoplastic Agents; D007143:Immunoglobulin Heavy Chains; D011506:Proteins; D025803:Tumor Suppressor Protein p14ARF