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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  ( Mcm4 D573H  ). 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  Mcm s, 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 MCM4 D573H  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.

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