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

Rachel E Rempel,Michele A Glozak,Joseph R Nevins,Seiichi Mori,Robert Storms,Nina M Laakso,Maura Gasparetto,Eran R Andrechek,Anand S Lagoo,Clay Smith,Steven B Adler,Jason D Lieb

doi:10.1371/journal.pgen.1000640

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.

Highlights

A hallmark of human cancer is genetic complexity, reflecting the acquisition of multiple mutations and gene rearrangements that give rise to the tumor phenotype
We found that tumor emergence was accelerated by E2F2 loss and delayed by E2F4 loss
We attributed these results to the finding that the mice lacking E2F2 have a greater proportion than usual of the most susceptible, early-stage B lineage cells and the mice lacking E2F4 have fewer of these cells

Summary

Introduction

A hallmark of human cancer is genetic complexity, reflecting the acquisition of multiple mutations and gene rearrangements that give rise to the tumor phenotype. Recent large-scale DNA sequencing efforts have provided direct evidence for this complexity, revealing large numbers of alterations that characterize various tumor types [1,2,3,4]. This genetic complexity of cancer underlies much of the challenge in developing effective therapeutic strategies. Mouse models of cancer have generally employed the use of an activated oncogene or the disruption of a tumor suppressor gene to initiate the oncogenic process This represents a defined genetic alteration, it is true that in most instances this single event is not sufficient to allow for tumor development. This can be seen in the often protracted latency of tumor development as well as the identification of specific additional genetic alterations that appear in these tumors

Methods

Results

Discussion

Conclusion