Runx2 and MYC collaborate in lymphoma development by suppressing apoptotic and growth arrest pathways in vivo.
Members of the Runx and MYC families have been implicated as collaborating oncogenes. The mechanism of this potent collaboration is elucidated in this study of Runx2/MYC mice. As shown previously, ectopic expression of Runx2 in the thymus leads to a preneoplastic state defined by an accumulation of cells with an immature phenotype and a low proliferative rate. We now show that c-MYC overexpression is sufficient to rescue proliferation and to release the differentiation block imposed by Runx2. Analysis of Runx2-expressing lymphomas reveals a consistently low rate of apoptosis, in contrast to lymphomas of MYC mice which are often highly apoptotic. The low apoptosis phenotype is dominant in Runx2/MYC tumors, indicating that Runx2 confers a potent survival advantage to MYC-expressing tumor cells. The role of the p53 pathway in Runx2/MYC tumors was explored on a p53 heterozygote background. Surprisingly, functional p53 was retained in vivo, even after transplantation, whereas explanted tumor cells displayed rapid allele loss in vitro. Our results show that Runx2 and MYC overcome distinct "fail-safe" responses and that their selection as collaborating genes is due to their ability to neutralize each other's negative growth effect. Furthermore, the Runx2/MYC combination overcomes the requirement for genetic inactivation of the p53 pathway in vivo.
Molecular Oncology Laboratory, Institute of Comparative Medicine, Faculty of Veterinary, Medicine, University of Glasgow, Glasgow, United Kingdom. K.Blyth@vet.gla.ac.uk
Karen
K
Blyth
François
F
Vaillant
Linda
L
Hanlon
Nancy
N
Mackay
Margaret
M
Bell
Alma
A
Jenkins
James C
JC
Neil
Ewan R
ER
Cameron
D000818:Animals; D017209:Apoptosis / Q000235:genetics; D002454:Cell Differentiation / Q000235:genetics; D048708:Cell Growth Processes / Q000235:genetics; D050659:Core Binding Factor Alpha 1 Subunit / Q000235:genetics*; D019941:Cyclin-Dependent Kinase Inhibitor p16; D005260:Female; D020868:Gene Silencing; D016399:Lymphoma, T-Cell / Q000235:genetics* / Q000473:pathology; D051379:Mice; D008822:Mice, Transgenic; D016271:Proto-Oncogene Proteins c-myc / Q000235:genetics*; D013601:T-Lymphocytes / Q000166:cytology; D025803:Tumor Suppressor Protein p14ARF / Q000096:biosynthesis / Q000235:genetics; D016159:Tumor Suppressor Protein p53 / Q000096:biosynthesis / Q000235:genetics
C417743:Cdkn2a protein, mouse; D050659:Core Binding Factor Alpha 1 Subunit; D019941:Cyclin-Dependent Kinase Inhibitor p16; C489428:Myc protein, mouse; D016271:Proto-Oncogene Proteins c-myc; C493716:Runx2 protein, mouse; D025803:Tumor Suppressor Protein p14ARF; D016159:Tumor Suppressor Protein p53