INK4a/ARF mutations accelerate lymphomagenesis and promote chemoresistance by disabling p53 |
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Authors: | Clemens A. Schmitt Mila E. McCurrach Elisa de Stanchina Rachel R. Wallace-Brodeur Scott W. Lowe |
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Affiliation: | Cold Spring Harbor Laboratory, Cold Spring Harbor, New York 11724, USA. |
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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. |
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