| First Author | Fusello A | Year | 2013 |
| Journal | Cell Cycle | Volume | 12 |
| Issue | 17 | Pages | 2867-75 |
| PubMed ID | 23966158 | Mgi Jnum | J:317301 |
| Mgi Id | MGI:6852288 | Doi | 10.4161/cc.25922 |
| Citation | Fusello A, et al. (2013) Histone H2AX suppresses translocations in lymphomas of Emu-c-Myc transgenic mice that contain a germline amplicon of tumor-promoting genes. Cell Cycle 12(17):2867-75 |
| abstractText | The DNA damage response (DDR) can restrain the ability of oncogenes to cause genomic instability and drive malignant transformation. The gene encoding the histone H2AX DDR factor maps to 11q23, a region frequently altered in human cancers. Since H2ax functions as a haploinsufficient suppressor of B lineage lymphomas with c-Myc amplification and/or translocation, we determined the impact of H2ax expression on the ability of deregulated c-Myc expression to cause genomic instability and drive transformation of B cells. Neither H2ax deficiency nor haploinsufficiency affected the rate of mortality of Emu-c-Myc mice from B lineage lymphomas with genomic deletions and amplifications. Yet H2ax functioned in a dosage-dependent manner to prevent unbalanced translocations in Emu-c-Myc tumors, demonstrating that H2ax functions in a haploinsufficient manner to suppress allelic imbalances and limit molecular heterogeneity within and among Emu-c-Myc lymphomas. Regardless of H2ax copy number, all Emu-c-Myc tumors contained identical amplification of chromosome 19 sequences spanning 20 genes. Many of these genes encode proteins with tumor-promoting activities, including Cd274, which encodes the PD-L1 programmed death ligand that induces T cell apoptosis and enables cancer cells to escape immune surveillance. This amplicon was in non-malignant B and T cells and non-lymphoid cells, linked to the Emu-c-Myc transgene, and associated with overexpression of PD-L1 on non-malignant B cells. Our data demonstrate that, in addition to deregulated c-Myc expression, non-malignant B lineage lymphocytes of Emu-c-Myc transgenic mice may have constitutive amplification and increased expression of other tumor-promoting genes. |
