Insertional Mutagenesis Reveals Progression Genes and Checkpoints in MYC/Runx2 Lymphomas

Abstract

In this study, we have exploited the power of insertional mutagenesis to elucidate tumor progression pathways in mice carrying two oncogenes (MYC/Runx2) that collaborate to drive early lymphoma development. Neonatal infection of these mice with Moloney murine leukemia virus resulted in accelerated tumor onset with associated increases in clonal complexity and lymphoid dissemination. Large-scale analysis of retroviral integration sites in these tumors revealed a profound bias towards a narrow range of target genes, including Jdp2 (Jundm2), D cyclin, and Pim family genes. Remarkably, direct PCR analysis of integration hotspots revealed that every progressing tumor consisted of multiple clones harboring hits at these loci, giving access to large numbers of independent insertion events and uncovering the contrasting mutagenic mechanisms operating at each target gene. Direct PCR analysis showed that high-frequency targeting occurs only in the tumor environment in vivo and is specific for the progression gene set. These results indicate that early lymphomas in MYC/Runx2 mice remain dependent on exogenous growth signals, and that progression can be achieved by constitutive activation of pathways converging on a cell cycle checkpoint that acts as the major rate-limiting step for lymphoma outgrowth. [Cancer Res 2007;67(11):5126-33]

Runx2 Regulates G Protein-coupled Signaling Pathways to Control Growth of Osteoblast Progenitors

“…Several other findings on Runx2 may illuminate this paradox. First, Runx2 has been characterized as a c-Myc cooperating oncogene in T cell lymphoma (16,71), and Runx2 expression is frequently elevated in osteosarcoma (6) 6 clearly suggesting that Runx2 may have pro-mitogenic functions apart from growth suppressive activities. Furthermore, our other studies suggest that Runx2 is up-regulated by mitogens in osteoblasts during early G 1 where it may have a positive role in cell proliferation (21).…”

“…Several studies indicate that Runx2 control of proliferation is cell type-specific. Runx2 inhibits proliferation of osteoprogenitors and committed osteoblasts (5,6), but it may have distinct biological roles in chondrocytes (2,6,13) and endothelial cells (14,15), as well as osteosarcoma cells (6,12), T cell lymphomas (16,17), and breast cancer (18). In non-osseous cells (e.g.…”

Ischemia-reperfusion injury up-regulates Pim-3 gene expression in myocardial tissue

“…Previously studies showed that the Pim kinases can inhibit apoptosis in tumor cells [16][17][18][19] . In our study, we found that Pim-3 gene silencing could not induce or facilitate H 2 O 2 -induced apoptosis in cardiomyocytes.…”

JDP2 (Jun Dimerization Protein 2)-deficient Mouse Embryonic Fibroblasts Are Resistant to Replicative Senescence

“…For example, JDP2 inhibits the Ras-dependent transformation of NIH3T3 cells (33), and disruption of the gene for JDP2 is often found in lymphomas that have been induced by insertional mutagenesis with Moloney murine leukemia virus in MYC/Runx2 transgenic mice (47). We propose that JDP2 not only inhibits the transformation of cells but also plays a role in the induction of senescence.…”