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.
Nilsson
Jonas A
JA
Department of Biochemistry, St. Jude Children's Research Hospital, Memphis, Tennessee 38105, USA.
Keller
Ulrich B
UB
Baudino
Troy A
TA
Yang
Chunying
C
Norton
Sara
S
Old
Jennifer A
JA
Nilsson
Lisa M
LM
Neale
Geoffrey
G
Kramer
Debora L
DL
Porter
Carl W
CW
Cleveland
John L
JL
D000818:Animals; D017209:Apoptosis / Q000187:drug effects; D001402:B-Lymphocytes / Q000737:chemistry / Q000187:drug effects / Q000378:metabolism; D018797:Cell Cycle Proteins / Q000235:genetics / Q000378:metabolism; D049109:Cell Proliferation / Q000187:drug effects; D019941:Cyclin-Dependent Kinase Inhibitor p16; D050759:Cyclin-Dependent Kinase Inhibitor p21; D050760:Cyclin-Dependent Kinase Inhibitor p27; D000518:Eflornithine / Q000494:pharmacology; D015870:Gene Expression / Q000187:drug effects; D015972:Gene Expression Regulation, Neoplastic / Q000187:drug effects; D006579:Heterozygote; D008223:Lymphoma / Q000188:drug therapy / Q000235:genetics / Q000378:metabolism*; D051379:Mice; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D008817:Mice, Mutant Strains; D008822:Mice, Transgenic; D009929:Organ Size / Q000187:drug effects; D009955:Ornithine Decarboxylase / Q000235:genetics / Q000378:metabolism*; D065108:Ornithine Decarboxylase Inhibitors; D011073:Polyamines / Q000378:metabolism; D016271:Proto-Oncogene Proteins c-myc / Q000235:genetics / Q000378:metabolism*; D013154:Spleen / Q000473:pathology; D015996:Survival Rate; D025803:Tumor Suppressor Protein p14ARF / Q000235:genetics / Q000378:metabolism; D025521:Tumor Suppressor Proteins / Q000235:genetics / Q000378:metabolism
C493957:Cdkn1a protein, mouse; C493961:Cdkn1b protein, mouse; C417743:Cdkn2a protein, mouse; D018797:Cell Cycle Proteins; D019941:Cyclin-Dependent Kinase Inhibitor p16; D050759:Cyclin-Dependent Kinase Inhibitor p21; C489428:Myc protein, mouse; D065108:Ornithine Decarboxylase Inhibitors; D011073:Polyamines; D016271:Proto-Oncogene Proteins c-myc; D025803:Tumor Suppressor Protein p14ARF; D025521:Tumor Suppressor Proteins; D050760:Cyclin-Dependent Kinase Inhibitor p27; D009955:Ornithine Decarboxylase; D000518:Eflornithine