Insertion of c-MycintoIghInduces B-Cell and Plasma-Cell Neoplasms in Mice

Abstract

We used gene targeting in mice to insert a His 6 -tagged mouse c-Myc cDNA, MycHis , head to head into the mouse immunoglobulin heavy-chain locus, Igh, just 5V of the intronic enhancer, EA. The insertion of Myc His mimicked both the human t(8;14)(q24;q32) translocation that results in the activation of MYC in human endemic Burkitt lymphomas and the homologous mouse T(12;15) translocation that deregulates Myc in certain mouse plasmacytomas. Beginning at the age of 6 months, MycHis transgenic mice developed Bcell and plasma neoplasms, such as IgM + lymphoblastic B-cell lymphomas, Bcl-6 + diffuse large B-cell lymphomas, and CD138 + plasmacytomas, with an overall incidence of 68% by 21 months. Molecular studies of lymphoblastic B-cell lymphoma, the most prevalent neoplasm (50% of all tumors), showed that the lymphomas were clonal, overexpressed Myc His , and exhibited the P2 to P1 promoter shift in Myc expression, a hallmark of MYC/Myc deregulation in human endemic Burkitt lymphoma and mouse plasmacytoma. Only 1 (6.3%) of 16 lymphoblastic B-cell lymphomas contained a BL-typical point mutation in the amino-terminal transactivation domain of Myc His , suggesting that most of these tumors are derived from naive, pregerminal center B cells. Twelve (46%) of 26 lymphoblastic B-cell lymphomas exhibited changes in the p19ArfMdm2-p53 tumor suppressor axis, an important pathway for Myc-dependent apoptosis. We conclude that Myc His insertion into Igh predictably induces B-cell and plasma-cell tumors in mice, providing a valuable mouse model for understanding the transformation-inducing consequences of the MYC/Mycactivating endemic Burkitt lymphoma t(8;14)/plasmacytoma T(12;15) translocation. (Cancer Res 2005; 65(4): 1306-15)

Transcription of a Productively Rearranged Ig VDJCα Does Not Require the Presence of HS4 in the Igh 3′ Regulatory Region

“…In other studies, c-myc was juxtaposed with the 3ЈRR both in transgenes and by genereplacement within the natural IgH and c-myc loci (19,36,37). In all of these cases, the result was deregulated expression of c-myc, supporting the notion that the 3ЈRR regulates not only the IgH promoters of assembled IgH genes but can also regulate the c-myc promoter(s) when c-myc insinuates itself into the Igh locus by chromosome translocation.…”

“…Chromosome translocations that juxtaposed the oncogene c-myc with the 3Ј end of the Igh locus, resulting in a promoter shift and deregulated c-myc expression, also compelled this search (35,36). Indeed, since the discovery of this first 3Ј IgH enhancer, there has accrued ample evidence that it, along with its neighbors (3ЈRR), play a role in both situations.…”

Molecular pathways in follicular lymphoma

“…However, the IgV H genes of these tumors appeared to be unmutated. 149,150 Similar to the other Emmyc induced lymphomas, in 12 of 26 BL-L the Arf-Mdm2-p53 pathway was deregulated. 149 Of note, in human BL the ARF-MDM2-P53 pathway is frequently disturbed due to deletions of ARF, elevated MDM2 levels or P53 mutations.…”

“…149,150 Similar to the other Emmyc induced lymphomas, in 12 of 26 BL-L the Arf-Mdm2-p53 pathway was deregulated. 149 Of note, in human BL the ARF-MDM2-P53 pathway is frequently disturbed due to deletions of ARF, elevated MDM2 levels or P53 mutations. [151][152][153] The transcriptional repressor BCL-6 is rearranged in B40% of human DLBCLs and in B5% of FLs (Table 1).…”

Epigenetic Control of Prolyl and Asparaginyl Hydroxylases in Prostate Cancer

“…Using the appropriate Cre-recombinase mouse, this model could be expanded to examining other elements of the immune system (e.g., B cells [68], neutrophils [69], macrophages [69]), different time points in development [41,42,70], or other organ systems altogether [53,71,72]. In addition, because of the simplicity of the breeding scheme the floxed SOD2 mouse may be applied in combination with other protein deletions or additions (e.g., p53 null [73], Myc overexpression [74,75]) to examine the effect of superoxide oxidative stress in alternative immune model systems. Overall, this new model and these observations serve as an initial step in understanding the role of ROS in development and function of mammalian organ systems.…”