title: Histone H2AX suppresses translocations in lymphomas of Eμ-c-Myc transgenic mice that contain a germline amplicon of tumor-promoting genes.
abstract: 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 Eμ-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 Eμ-c-Myc tumors, demonstrating that H2ax functions in a haploinsufficient manner to suppress allelic imbalances and limit molecular heterogeneity within and among Eμ-c-Myc lymphomas. Regardless of H2ax copy number, all Eμ-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 Eμ-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 Eμ-c-Myc transgenic mice may have constitutive amplification and increased expression of other tumor-promoting genes.
authors: Division of Cancer Pathobiology; Department of Pathology and Laboratory Medicine; Center for Childhood Cancer Research; Children's Hospital of Philadelphia Research Institute; Philadelphia, PA USA; Abramson Family Cancer Research Institute; Perelman School of Medicine of the University of Pennsylvania; Philadelphia, PA USA.
authors: Angela
authors: A
authors: Fusello
authors: Julie
authors: J
authors: Horowitz
authors: Katherine
authors: K
authors: Yang-Iott
authors: Brenna L
authors: BL
authors: Brady
authors: Bu
authors: B
authors: Yin
authors: Marta A W
authors: MA
authors: Rowh
authors: Eric
authors: E
authors: Rappaport
authors: Craig H
authors: CH
authors: Bassing
mesh_terms: D000818:Animals; D001402:B-Lymphocytes / Q000378:metabolism / Q000473:pathology; D019070:Cell Lineage / Q000235:genetics; D033481:Chromosomes, Mammalian / Q000378:metabolism; D002999:Clone Cells; D055028:Comparative Genomic Hybridization; D005784:Gene Amplification / Q000235:genetics; D017353:Gene Deletion; D005854:Germ Cells / Q000378:metabolism*; D057895:Haploinsufficiency / Q000235:genetics; D006657:Histones / Q000378:metabolism*; D006801:Humans; D008223:Lymphoma / Q000235:genetics* / Q000473:pathology; D051379:Mice; D008810:Mice, Inbred C57BL; D008822:Mice, Transgenic; D009857:Oncogenes / Q000235:genetics*; D016271:Proto-Oncogene Proteins c-myc / Q000235:genetics*; D013489:Suppression, Genetic; D019076:Transgenes / Q000235:genetics; D014178:Translocation, Genetic
chemical_list: D006657:Histones; D016271:Proto-Oncogene Proteins c-myc; C475961:gamma-H2AX protein, mouse
keywords: DNA damage response; Eμ-c-Myc transgenic mice; genomic instability; histone H2AX; lymphoma
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