Subject(s)
Adaptor Proteins, Signal Transducing/genetics , DNA Repair/genetics , Nuclear Proteins/genetics , Precursor T-Cell Lymphoblastic Leukemia-Lymphoma/genetics , T-Lymphocytes/metabolism , Adaptor Proteins, Signal Transducing/metabolism , Animals , Exons/genetics , Gene Deletion , Mice , Mice, Knockout , MutL Protein Homolog 1 , Nuclear Proteins/metabolism , Precursor T-Cell Lymphoblastic Leukemia-Lymphoma/metabolism , Precursor T-Cell Lymphoblastic Leukemia-Lymphoma/pathology , T-Lymphocytes/pathology , Thymus Gland/metabolism , Thymus Gland/pathologyABSTRACT
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.
