Combined deletion of Xrcc4 and Trp53 in mouse germinal center B cells leads to novel B cell lymphomas with clonal heterogeneity

Abstract

BackgroundActivated B lymphocytes harbor programmed DNA double-strand breaks (DSBs) initiated by activation-induced deaminase (AID) and repaired by non-homologous end-joining (NHEJ). While it has been proposed that these DSBs during secondary antibody gene diversification are the primary source of chromosomal translocations in germinal center (GC)-derived B cell lymphomas, this point has not been directly addressed due to the lack of proper mouse models.MethodsIn the current study, we establish a unique mouse model by specifically deleting a NHEJ gene, Xrcc4, and a cell cycle checkpoint gene, Trp53, in GC B cells, which results in the spontaneous development of B cell lymphomas that possess features of GC B cells.ResultsWe show that these NHEJ deficient lymphomas harbor translocations frequently targeting immunoglobulin (Ig) loci. Furthermore, we found that Ig translocations were associated with distinct mechanisms, probably caused by AID- or RAG-induced DSBs. Intriguingly, the AID-associated Ig loci translocations target either c-myc or Pvt-1 locus whereas the partners of RAG-associated Ig translocations scattered randomly in the genome. Lastly, these NHEJ deficient lymphomas harbor complicated genomes including segmental translocations and exhibit a high level of ongoing DNA damage and clonal heterogeneity.ConclusionsWe propose that combined NHEJ and p53 defects may serve as an underlying mechanism for a high level of genomic complexity and clonal heterogeneity in cancers.Electronic supplementary materialThe online version of this article (doi:10.1186/s13045-015-0230-5) contains supplementary material, which is available to authorized users.

HDAC inhibitors overcome immunotherapy resistance in B-cell lymphoma

“…Overcome immunotherapy resistance in B-cell lymphoma REVIEW classical Hodgkin lymphoma (HL) present the loss of MHC class I expression (Challa-Malladi et al, 2011;de Charette and Houot, 2018), and diminished MHC class II expression also frequently occurs not only in DLBCL but also in other types of mature B-cell lymphomas (Rimsza et al, 2004;Roberts et al, 2006;Diepstra et al, 2007a;Fangazio et al, 2014;de Charette et al, 2016;Nijland et al, 2017). We recently established a unique mouse model by lineagespecific deletion of a DNA repair gene, Xrcc4, and Trp53 in GC B cells (Chen et al, 2016). This mouse strain spontaneously develops mature B-cell lymphomas, termed G1XP lymphomas (Chen et al, 2016).…”

“…We recently established a unique mouse model by lineagespecific deletion of a DNA repair gene, Xrcc4, and Trp53 in GC B cells (Chen et al, 2016). This mouse strain spontaneously develops mature B-cell lymphomas, termed G1XP lymphomas (Chen et al, 2016). G1XP lymphomas resemble the key features of human B-cell lymphomas including reciprocal chromosomal translocations and elevated expression of c-myc (Chen et al, 2016) and downregulation of MHC class I and class II expression (Wang et al, 2019).…”

Histone Deacetylase Inhibition Sensitizes PD1 Blockade–Resistant B-cell Lymphomas

“…G1XP lymphomas were generated, established, and cultured as described previously (8). A20 lymphoma cells were obtained from cell line vendor ATCC in 2017.…”

“…There are no good experimental models to study PD1 blockade resistance observed in human Bcell lymphomas. To address these issues, we employed a mouse mature B-cell lymphoma model, G1XP (8), which resembles human B-cell lymphomas, to test therapeutic strategies.…”

“…In this study, we employed an HDACi (OKI-179) and G1XP lymphoma (8), created by lineage-specific deletion of a DNA repair gene, Xrcc4, and Trp53 in germinal center (GC) B cells, because most human mature B-cell lymphomas are derived from GC or post-GC B cells (51). We show that G1XP lymphomas downregulated their MHC expression and resisted anti-PD1.…”