Figure 1. Loss of Rassf1a promotes tumorigenesis.

A. Kaplan-Meier curves showing the tumor latency for Rassf1a^+/+ and Rassf1a^−/− mice on a ‘jumping’ background (i.e., T2Onc^+/Tg; Rosa^+/SB) are significantly different using the Log-rank (Mantel-Cox) Test: P<0.0009. B. Photomicrographs of formalin-fixed, hematoxylin and eosin-stained sections of (i) a thymic lymphoma (ii) that metastasized to the liver; (iii) a splenic lymphoma (iv) that metastasized to the lung; a leukemia that infiltrated the (v) spleen and (vi) kidney; and a mouse that developed two independent tumors, specifically (vii) splenic lymphoma and (viii) hepatocellular carcinoma. C. Photomicrographs of an immunohistochemically-stained (i) lung section infiltrated by a lymphoma of T-cell origin (CD3-positive), and (ii) a spleen section infiltrated by myeloid leukemia (MPO-positive). All sections shown are representative and images are at x400 magnification. D. Seven of the Rassf1a^−/− SB mice that developed leukemia/lymphoma carried transposons which had inserted into the Runx2 gene (indicated by the red triangles; direction of triangle indicates orientation of the transposon). The blue triangles are Rassf1a^+/+ SB mice that developed leukemia/lymphoma and carried Runx2 insertions, although these insertions did not constitute a statistically significant common insertion site (CIS). Sequencing of the insertion-genome junction from splenic cDNA of two of these mice showed the splicing of Runx2 directly onto the splice acceptor (SA)-polyA from the transposon. The protein structure of RUNX2 is shown in blue and the key domains are labeled, including a glutamine/alanine (QA) rich tract, a Runt domain (RHD), a nuclear localization signal (NLS), a proline/serine/threonine (PST) rich tract, a nuclear matrix targeting signal (NMTS) and the C-terminal VWRPY domain for TLE/Groucho co-repressor interactions.