Runx2 and MYC Collaborate in Lymphoma Development by Suppressing Apoptotic and Growth Arrest Pathways In vivo

Abstract

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. (Cancer Res 2006; 66(4): 2195-201)

Combination of Runx2 and BMP2 increases conversion of human ligamentum flavum cells into osteoblastic cells

“…Runx2 is known as an important regulator of cell proliferation, and its ablation increases the growth of cultured cells (15,(19)(20)(21). On the other hand, forced expression of Runx2 suppresses proliferation of osteoblasts (15,22) and non-osteogenic cells (23). Hence, Runx2 has been proposed as a gene related to cancer (24).…”

Runx2 deficiency and defective subnuclear targeting bypass senescence to promote immortalization and tumorigenic potential

“…Notwithstanding the evident roles of Runx proteins in limiting cell proliferation, Runx2 also has been identified as an oncogene that cooperates with Myc in the etiology of T cell lymphomas (Til-1) (34). Furthermore, Runx2 is elevated and deregulated in osteosarcomas and is ectopically expressed in metastatic breast and prostate tumor cells (26)(27)(28).…”

Molecular profiling of CD3−CD4+ T cells from patients with the lymphocytic variant of hypereosinophilic syndrome reveals targeting of growth control pathways

“…The Runx genes have been shown to function as tumor suppressors in human cancer, although their overexpression in murine models revealed an oncogenic role in the development of hematopoietic tumors, including T lymphomas. 41 Runx2 mediates cellular responses to signaling pathways hyperactive in tumors, including TGF-␤ family pathways, by forming coregulatory complexes with Smads and other coactivator and corepressor proteins to regulate gene transcription. Runx2, better known for its role in bone development and maintenance, was up-regulated in all patients and then again during P1's evolution to T lymphoma (Table 1).…”