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

Genes Dev. 1999 Oct 15;13(20):2670-7. doi: 10.1101/gad.13.20.2670.

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.

Publication types

  • Research Support, Non-U.S. Gov't
  • Research Support, U.S. Gov't, P.H.S.

MeSH terms

  • Animals
  • Antineoplastic Agents / pharmacology
  • Apoptosis / genetics
  • Drug Resistance / genetics
  • Enhancer Elements, Genetic
  • Female
  • Genes, myc
  • Genes, p16*
  • Genes, p53*
  • Humans
  • Immunoglobulin Heavy Chains / genetics
  • Lymphoma, B-Cell / drug therapy
  • Lymphoma, B-Cell / etiology*
  • Lymphoma, B-Cell / genetics*
  • Male
  • Mice
  • Mice, Inbred C57BL
  • Mice, Knockout
  • Mice, Transgenic
  • Mutation*
  • Proteins / genetics*
  • Tumor Suppressor Protein p14ARF

Substances

  • Antineoplastic Agents
  • Immunoglobulin Heavy Chains
  • Proteins
  • Tumor Suppressor Protein p14ARF