A Dominantly Acting Murine Allele of Mcm4 Causes Chromosomal Abnormalities and Promotes Tumorigenesis

Bruce N Bagley,Robert T Cormier,Scott C Kogan,David J Adams,Thomas M Keane,Lara S Collier,Michelle M Cancel,Christina Kendziorski,Laura E Bendzick,Raha A Been,Jonathon G Marshall,Rachael A Lester,Vilena I Maklakova,Alex R Paulsen

doi:10.1371/journal.pgen.1003034

Abstract

Here we report the isolation of a murine model for heritable T cell lymphoblastic leukemia/lymphoma (T-ALL) called Spontaneous dominant leukemia (Sdl). Sdl heterozygous mice develop disease with a short latency and high penetrance, while mice homozygous for the mutation die early during embryonic development. Sdl mice exhibit an increase in the frequency of micronucleated reticulocytes, and T-ALLs from Sdl mice harbor small amplifications and deletions, including activating deletions at the Notch1 locus. Using exome sequencing it was determined that Sdl mice harbor a spontaneously acquired mutation in Mcm4 (Mcm4D573H). MCM4 is part of the heterohexameric complex of MCM2–7 that is important for licensing of DNA origins prior to S phase and also serves as the core of the replicative helicase that unwinds DNA at replication forks. Previous studies in murine models have discovered that genetic reductions of MCM complex levels promote tumor formation by causing genomic instability. However, Sdl mice possess normal levels of Mcms, and there is no evidence for loss-of-heterozygosity at the Mcm4 locus in Sdl leukemias. Studies in Saccharomyces cerevisiae indicate that the Sdl mutation produces a biologically inactive helicase. Together, these data support a model in which chromosomal abnormalities in Sdl mice result from the ability of MCM4D573H to incorporate into MCM complexes and render them inactive. Our studies indicate that dominantly acting alleles of MCMs can be compatible with viability but have dramatic oncogenic consequences by causing chromosomal abnormalities.

Highlights

Mouse models have been invaluable tools for studying human cancer
Our study investigated a spontaneous mouse model for dominantly inherited T-cell leukemia/lymphoma
This Mcm4 allele promotes the accumulation of focal chromosomal gains and losses, including aberrations at the Notch1 locus that drive the formation of T-cell leukemia/lymphoma

Summary

Introduction

Mouse models have been invaluable tools for studying human cancer. Many mouse models used for this purpose are reverse genetic, in that they involve genetically modified mice engineered to have lost a specific tumor suppressor gene (tsg) or to overexpress a specific proto-oncogene. Spontaneous or mutagen induced mouse models that result in tumor formation have been used to study tumorigenesis. Given the contribution of mouse models to understanding tumorigenesis, when a spontaneous mouse mutant that developed T-ALL arose in our colony, we pursued studies to both characterize the disease in these mice and to identify the causal mutation. The mutation was spontaneous and the phenotype dominant, so we named the mutant Spontaneous dominant leukemia (Sdl). We have identified a mutation in the Mcm gene as the likely causative genetic lesion in these mice

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Conclusion