Open AccessINK4a/ARF mutations accelerate lymphomagenesis and promote chemoresistance by disabling p53
Author(s) -
Clemens A. Schmitt,
Mila E. McCurrach,
Elisa de Stanchina,
R. R. Wallace-Brodeur,
Scott W. Lowe
Publication year - 1999
Publication title -
genes and development
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 7.136
H-Index - 438
eISSN - 1549-5477
pISSN - 0890-9369
DOI - 10.1101/gad.13.20.2670
Subject(s) - biology , cancer research , suppressor , lymphoma , tumor suppressor gene , gene , retinoblastoma , transgene , locus (genetics) , in vivo , carcinogenesis , genetics , immunology
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.