A Role for E2F Activities in Determining the Fate of Myc-Induced Lymphomagenesis

Abstract

The phenotypic heterogeneity that characterizes human cancers reflects the enormous genetic complexity of the oncogenic process. This complexity can also be seen in mouse models where it is frequently observed that in addition to the initiating genetic alteration, the resulting tumor harbors additional, somatically acquired mutations that affect the tumor phenotype. To investigate the role of genetic interactions in the development of tumors, we have made use of the Eμ-myc model of pre-B and B cell lymphoma. Since various studies point to a functional interaction between Myc and the Rb/E2F pathway, we have investigated the role of E2F activities in the process of Myc-induced lymphomagenesis. Whereas the absence of E2F1 and E2F3 function has no impact on Myc-mediated tumor development, the absence of E2F2 substantially accelerates the time of tumor onset. Conversely, tumor development is delayed by the absence of E2F4. The enhanced early onset of tumors seen in the absence of E2F2 coincides with an expansion of immature B lineage cells that are likely to be the target for Myc oncogenesis. In contrast, the absence of E2F4 mutes the response of the lineage to Myc and there is no expansion of immature B lineage cells. We also find that distinct types of tumors emerge from the Eμ-myc mice, distinguished by different patterns of gene expression, and that the relative proportions of these tumor types are affected by the absence of either E2F2 or E2F4. From these results, we conclude that there are several populations of tumors that arise from the Eμ-myc model, reflecting distinct populations of cells that are susceptible to Myc-mediated oncogenesis and that the proportion of these cell populations is affected by the presence or absence of E2F activities.

Prediction and Genetic Demonstration of a Role for Activator E2Fs in Myc-Induced Tumors

“…Specifically, we noted a role for E2Fs in an EmMyc lymphomagenesis model (18) and in a K5-Myc skin epithelial model (19). Briefly, in the Em-Myc model, tumors were generated on various E2F mutant backgrounds, illustrating that of the activator E2Fs, only E2F2 altered tumor latency and in opposition to what we observed, loss of E2F2 accelerated tumor formation.…”

“…Any impact on tumor development in the absence of an E2F should be considered in the light of these findings. Interestingly, a recent study on the role of the E2Fs in Mycinduced tumors in the lymphatic system revealed individual roles for the E2Fs, largely dependent upon the context of expression (18). In short, it was concluded that loss of E2F2 accelerated tumor formation in that tissue.…”

E2F4 plays a key role in Burkitt lymphoma tumorigenesis

“…33 There is no conflict, however, because while the Em-myc mouse is useful to study the role of c-myc in lymphomagenesis, 34 this mouse is not a BL model. Indeed, Em-myc mice develop primarily pre-B-cell tumors whose histopathologic features are consistent with the diagnosis of lymphoblastic lymphoma rather than BL.…”

Links between metabolism and cancer

“…Myc further stimulates genes involved in nucleotide metabolism and specifically interacts with the E2F family of transcription factors to drive proliferating cells into S phase for DNA replication (Leone et al 2001;Zeller et al 2006;Rempel et al 2009). As a pleiotropic transcription factor, Myc also directly stimulates cell cycle regulatory genes and those directly involved in DNA replication, such as CDK4, CDK6, and MCM genes .…”