Project description:Germinal center (GC) B cells have been presented as the cell-of-origin of diffuse large B-cell lymphoma (DLBCL), and these cells can be functionally targeted with the use of Cgamma1-cre mice (Cg1cre) in wich the expression of Cre recombinase is induced by transcription of the Ig gamma1 constant region gene segment. Here, we aimed to develop and characterize novel immunocompetent multi-lesion mouse models of DLBCL that, by triggering genetic alterations specifically in GC B cells, recapitulate relatively fast the molecular, cellular and tumor microenvironment of aggressive human DLBCL.
Project description:We have developed a novel immunocompetent multi-lesion mouse model of activated B cell diffuse large B-cell lymphoma (ABC-DLBCL; the pBIC mice) that recapitulates relatively fast the molecular, cellular and tumor microenvironment of aggressive human ABC-DLBCL. We demonstrate that perturbed p53 signaling cooperates with constitutive NF-kB activation in GC-experienced plasmablasts with blocked terminal differentiation to promote lymphomagenesis and tumor progression through triggering downstream intracellular molecular addictions (e.g. deregulating Foxp1 and AID pathways) and intercellular immunosuppressive signals for evading anti-tumoral responses (e.g. MHC-II antigen presentation and deregulating PD-L1/PD-1 immune checkpoint). Our immunocompetent ABC-DLBCL murine model provides in vivo evidence that PD-1 blockade cooperates with anti-CD20-based current standard-of-care therapy to reshape the immunosuppressive TME and facilitate long-term anti-tumoral responses. Therefore, our results support that immune checkpoints may hold promising therapeutic potential in ABC-DLBCL.
Project description:Transcriptional profiling Myc-driven lymphomas to determine pathways by which Wrn deficiency impairs tumor development Total RNA isolated from Eµ-Myc and Eµ-Myc Wrn Δhel/Δhel murine B-cell lymphomas (n=4)
Project description:To analyze expression differences between Trp53 pro-and deficient as well as Atm pro- and deficient murine CLL tumors developing in the Eµ-TCL1 mouse model, we analyzed splenocytes isolated from heavily infiltrated spleens of sick mice. To investigate differences in the response to cyclophosphamide, we also analyzed splenocytes from leukemic animals that were isolated twelve hours after intraperitoneal injection of cyclophosphamide.
Project description:We have developed a novel immunocompetent multi-lesion mouse model of activated B cell diffuse large B-cell lymphoma (ABC-DLBCL; the pBIC mice) that recapitulates relatively fast the molecular, cellular and tumor microenvironment of aggressive human ABC-DLBCL. We demonstrate that perturbed p53 signaling cooperates with constitutive NF-kB activation in GC-experienced plasmablasts with blocked terminal differentiation to promote lymphomagenesis and tumor progression through triggering downstream intracellular molecular addictions (e.g. deregulating Foxp1 and AID pathways) and intercellular immunosuppressive signals for evading anti-tumoral responses (e.g. MHC-II antigen presentation and deregulating PD-L1/PD-1 immune checkpoint). Our immunocompetent ABC-DLBCL murine model provides in vivo evidence that PD-1 blockade cooperates with anti-CD20-based current standard-of-care therapy to reshape the immunosuppressive TME and facilitate long-term anti-tumoral responses. Therefore, our results support that immune checkpoints may hold promising therapeutic potential in ABC-DLBCL.
Project description:Germinal center (GC) B cells have been presented as the cell-of-origin of diffuse large B-cell lymphoma (DLBCL), and these cells can be functionally targeted with the use of Cgamma1-cre mice (Cg1cre) in wich the expression of Cre recombinase is induced by transcription of the Ig gamma1 constant region gene segment. Here, we aimed to develop and characterize novel immunocompetent multi-lesion mouse models of DLBCL that, by triggering genetic alterations specifically in GC B cells, recapitulate relatively fast the molecular, cellular and tumor microenvironment of aggressive human DLBCL.