Abstract A37: A dominantly acting allele of murine Mcm4 causes chromosome instability and promotes leukemiogenesis

Abstract

Abstract Mouse models have been invaluable tools for studying human cancer. Given the contribution of mouse models to understanding tumorigenesis, when a spontaneous mouse mutant that developed heritable T cell lymphoblastic leukemia/lymphoma (T-ALL) arose in our colony, we pursued studies to both characterize the disease in these mice and to identify the mutant gene responsible for the phenotype. Because the mutation was spontaneous and the phenotype was dominant, we named the mutant Spontaneous dominant leukemia (Sdl). Sdl heterozygous mice develop disease with short latency and high penetrance; while mice homozygous for the mutation die early during embryonic development. We have discovered a spontaneously acquired mutation in Mcm4 in Sdl mice by whole exome sequencing. 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 the replication fork. Previous studies in murine models have discovered that reduced levels of MCM complexes resulting from hypomorphic Mcm alleles 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; indicating that the Sdl Mcm4 allele is not a hypomorphic or loss-of-function allele. Sdl mice harbor increased numbers of spontaneous micronuclei and Sdl T-ALLs are characterized by intragenic deletions at the Notch1 locus. Therefore, our studies indicate that dominantly acting alleles of MCMs can be compatible with viability but have dramatic oncogenic consequences caused by chromosome instability. Citation Format: {Authors}. {Abstract title} [abstract]. In: Proceedings of the Second AACR International Conference on Frontiers in Basic Cancer Research; 2011 Sep 14-18; San Francisco, CA. Philadelphia (PA): AACR; Cancer Res 2011;71(18 Suppl):Abstract nr A37.