Scientists at St. Jude Childrens Research Hospital have discovered that a single defective copy of the gene, Dmp1, is sufficient to drive cancer development in a mouse model of B-cell lymphoma.
Although one half of human cancers have mutations in the tumor suppressor gene, p53, half do not. Using a murine model of B-cell lymphoma, Dr. Charles Sherr and colleagues have discovered that the mutation of a single allele, or copy, of the Dmp1 gene is sufficient to drive lymphomagenesis in cells that retain normal p53 status.
Published in Genes & Development, this discovery represents a major breakthrough in the determination of the genetic factors that underlie tumor development in cells in which the more common tumor suppressor genes, like p53, are not mutated.
Dr. Sherr and colleagues studied tumor progression in a transgenic mouse strain that specifically over-expresses the Myc oncogene in lymphoid B cells. The abnormally high expression of Myc in lymphoid B cells induces lymphoma development and leukemia. The tumors that develop in these Myc transgenic mice often also have spontaneous mutations in p53 or Arf, which regulates p53.
This spontaneous loss of p53 or Arf is the result of a selection process occurring within the population of cancerous cells: A cell which disables p53 or Arf loses its anti-proliferative regulatory mechanism, and thus is better adapted to reproduce. However, about 25% of the lymphomas in these Myc transgenic mice do not display alterations in p53 or its interacting proteins. Dr. Sherr and colleagues have discovered why.
Dr. Sherr and colleagues have found that if the Myc-induced murine lymphoma has even one defective copy of the Dmp1 gene, this genetic mutation is powerful enough to drive tumor progression. The power behind Dmp1 lies in its normal physiological role.
Dmp1 activates Arf expression, which, under oncogenic conditions (like Myc over-expression), in turn enhances p53 activity and
Contact: Nora Poppito
Cold Spring Harbor Laboratory