Targeting ornithine decarboxylase in Myc-induced lymphomagenesis prevents tumor formation.

• Checkpoints that control Myc-mediated proliferation and apoptosis are bypassed during tumorigenesis. Genes encoding polyamine biosynthetic enzymes are overexpressed in B cells from E mu-Myc transgenic mice. Here, we report that disabling one of these Myc targets, Ornithine decarboxylase (Odc), abolishes Myc-induced suppression of the Cdk inhibitors p21(Cip1) and p27(Kip1), thereby impairing Myc's proliferative, but not apoptotic, response. Moreover, lymphoma development was markedly delayed in E mu-Myc;Odc(+/-) transgenic mice and in E mu-Myc mice treated with the Odc inhibitor difluoromethylornithine (DFMO). Strikingly, tumors ultimately arising in E mu-Myc;Odc(+/-) transgenics lacked deletions of Arf, suggesting that targeting Odc forces other routes of transformation. Therefore, Odc is a critical Myc transcription target that regulates checkpoints that guard against tumorigenesis and is an effective target for cancer chemoprevention.

Keyword

Animals

Apoptosis/drug effects

B-Lymphocytes/chemistry/drug effects/metabolism

Cell Cycle Proteins/genetics/metabolism

Cell Proliferation/drug effects

Cyclin-Dependent Kinase Inhibitor p16

Cyclin-Dependent Kinase Inhibitor p21

Cyclin-Dependent Kinase Inhibitor p27

Eflornithine/pharmacology

Gene Expression/drug effects

Gene Expression Regulation; Neoplastic/drug effects

Heterozygote

Lymphoma/drug therapy/genetics/*metabolism

Mice

Mice; Inbred C57BL

Mice; Knockout

Mice; Mutant Strains

Mice; Transgenic

Organ Size/drug effects

Ornithine Decarboxylase/antagonists & inhibitors/genetics/*metabolism

Polyamines/metabolism

Proto-Oncogene Proteins c-myc/genetics/*metabolism

Spleen/pathology

Survival Rate

Tumor Suppressor Protein p14ARF/genetics/metabolism

Tumor Suppressor Proteins/genetics/metabolism

Publication and Content Type

ref (subject category)

art (subject category)