title: Mcm2 deficiency results in short deletions allowing high resolution identification of genes contributing to lymphoblastic lymphoma.
abstract: Mini-chromosome maintenance (Mcm) proteins are part of the replication-licensing complex that is loaded onto chromatin during the G1-phase of the cell cycle and required for initiation of DNA replication in the subsequent S-phase. Mcm proteins are typically loaded in excess of the number of locations that are used during S-phase. Nonetheless, partial depletion of Mcm proteins leads to cancers and stem cell deficiencies. Mcm2 deficient mice, on a 129Sv genetic background, display a high rate of thymic lymphoblastic lymphoma. Here array comparative genomic hybridization is used to characterize the genetic damage accruing in these tumors. The predominant events are deletions averaging less than 0.5 Mbp, considerably shorter than observed in prior studies using alternative mouse lymphoma models or human tumors. Such deletions facilitate identification of specific genes and pathways responsible for the tumors. Mutations in many genes that have been implicated in human lymphomas are recapitulated in this mouse model. These features, and the fact that the mutation underlying the accelerated genetic damage does not target a specific gene or pathway a priori, are valuable features of this mouse model for identification of tumor suppressor genes. Genes affected in all tumors include Pten, Tcfe2a, Mbd3 and Setd1b. Notch1 and additional genes are affected in subsets of tumors. The high frequency of relatively short deletions is consistent with elevated recombination between nearby stalled replication forks in Mcm2-deficient mice.
authors.affiliation: Department of Molecular and Cellular Biology, Roswell Park Cancer Institute, Buffalo, NY 14263, USA.
authors.forename: M E
authors.initials: ME
authors.lastname: Rusiniak
authors.forename: D
authors.initials: D
authors.lastname: Kunnev
authors.forename: A
authors.initials: A
authors.lastname: Freeland
authors.forename: G K
authors.initials: GK
authors.lastname: Cady
authors.forename: S C
authors.initials: SC
authors.lastname: Pruitt
mesh_terms: D000818:Animals; D001483:Base Sequence; D018797:Cell Cycle Proteins / Q000172:deficiency* / Q000235:genetics; D056905:Chromosome Breakpoints; D033481:Chromosomes, Mammalian / Q000235:genetics; D055028:Comparative Genomic Hybridization; D056915:DNA Copy Number Variations; D052138:Genes, Neoplasm; D006801:Humans; D051379:Mice; D057507:Mice, 129 Strain; D008810:Mice, Inbred C57BL; D064111:Minichromosome Maintenance Complex Component 2; D008969:Molecular Sequence Data; D009687:Nuclear Proteins / Q000172:deficiency* / Q000235:genetics; D054218:Precursor T-Cell Lymphoblastic Leukemia-Lymphoma / Q000235:genetics*; D017422:Sequence Analysis, DNA; D017384:Sequence Deletion; D013953:Thymus Neoplasms / Q000235:genetics*
chemical_list: D018797:Cell Cycle Proteins; C576318:Mcm2 protein, mouse; D009687:Nuclear Proteins; D064111:Minichromosome Maintenance Complex Component 2