title: Msh2-dependent DNA repair mitigates a unique susceptibility of B cell progenitors to c-Myc-induced lymphomas.
abstract: C-Myc is one of the most common targets of genetic alterations in human cancers. Although overexpression of c-Myc in the B cell compartment predisposes to lymphomas, secondary mutations are required for disease manifestation. In this article, we show that genetic deficiencies causing arrested B cell development and accumulation of B cell progenitors lead to accelerated lymphomagenesis in Emu c-myc transgenic mice. This result suggests that B cell progenitors are more prone than their mature counterparts to developing secondary oncogenic lesions that complement c-Myc in promoting transformation. To investigate the nature of these oncogenic lesions, we examined Emu c-myc mice deficient in mismatch repair function. We report that Msh2(-/-) Emu c-myc and Msh2(G674A/G674A) Emu c-myc mice rapidly succumb to pro-B cell stage lymphomas, indicating that Msh2-dependent mismatch repair function actively suppresses c-Myc-associated oncogenesis during early B cell development.
authors.affiliation: Department of Immunology, University of Toronto, Medical Sciences Building, Toronto, Canada.
authors.forename: Rajeev M
authors.initials: RM
authors.lastname: Nepal
authors.forename: Li
authors.initials: L
authors.lastname: Tong
authors.forename: Blerta
authors.initials: B
authors.lastname: Kolaj
authors.forename: Winfried
authors.initials: W
authors.lastname: Edelmann
authors.forename: Alberto
authors.initials: A
authors.lastname: Martin
mesh_terms: D000818:Animals; D017209:Apoptosis; D004260:DNA Repair; D004198:Disease Susceptibility; D008223:Lymphoma / Q000276:immunology* / Q000473:pathology*; D051379:Mice; D008810:Mice, Inbred C57BL; D008822:Mice, Transgenic; D051718:MutS Homolog 2 Protein / Q000172:deficiency / Q000378:metabolism*; D054448:Precursor Cells, B-Lymphoid / Q000276:immunology / Q000473:pathology*; D016271:Proto-Oncogene Proteins c-myc / Q000378:metabolism*; D016159:Tumor Suppressor Protein p53 / Q000378:metabolism
chemical_list: D016271:Proto-Oncogene Proteins c-myc; D016159:Tumor Suppressor Protein p53; C497173:Msh2 protein, mouse; D051718:MutS Homolog 2 Protein