INK4a/ARF mutations accelerate lymphomagenesis and promote chemoresistance by disabling p53

作者：Clemens A. Schmitt, Mila E. McCurrach, Elisa de Stanchina, R. R. Wallace-Brodeur, Scott W. Lowe · 发表于：Genes & Development · 年份：1999 · DOI：10.1101/gad.13.20.2670 · 被引用次数：463 · 研究领域：Cancer-related Molecular Pathways、interferon and immune responses、Cell death mechanisms and regulation

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.