Core 1: Lymphoma models

CORE 1 LYMPHOMA MODEL SYSTEMS: SUMMARY/ABSTRACT The Lymphoma Model System core (LMSC) will assemble and characterize the reagents critical for this proposal, including the vast array of engineered mouse models (GEMM), clinically and molecularly annotated primary samples, patient-derived tumor xenograft (PDX), and PDX-derived cell models, as well as patient- derived organoids (PDOs). These resources will be provided to project leaders to define the pathogenetic role of selected lesions and to identify their relevance in the genesis and maintenance of Diffuse Large B-Cell Lymphomas (DLBCL), taking advantage of innovative in-vitro and in-vivo platforms. We predict that the services of the LMSC will provide the basis for the biological dissection of the genetic lesions described in all Projects, leading to a deeper knowledge of how 3D genome organization plays a role in gene regulation and in oncogenic transcriptional programs. We anticipate assembling a relatively large library of PDX representative of DLBCL neoplasms carrying defects that impair chromatin organization and gene expression. To achieve these objectives, we will integrate multiple platforms taking advantage of conventional morphology with a large battery of antibodies and molecular-based approaches (WES, RNAseq, etc.) to define the natural evolution of lymphoid elements carrying ad hoc defects, stratify the emerging neoplasms in PDX and humanized models and correlate them with those detected in primary neoplasms. Importantly, primary 2D and 3D cultures and tumor xenografts have been tested, showing that they essentially mimic the original patient tumor, including tumor heterogeneity, and they can effectively predict response to therapies. Of note, models from primary patient-derived cultures or PDX have proven to be more informative than conventional cell lines allowing precise determinations and more reliable assessments. As many as 85% of drugs within in vitro activity in established cell lines have failed in human studies, primarily because of a lack of efficacy in complex systems or human settings. Having decided to interrogate defects that can be observed in unique/rare neoplasms and test the specific relationships between host and lymphoma elements in young and older individuals, we will take advantage of the lentiviral-mediated system to create ad hoc models (Project 3). Thus, our models are beneficial for in vivo mechanistic studies (all projects). The information they provide will be instrumental in understanding the pathogenetic potential of the defects investigated in this application, leading to potential targeted therapies (Projects 1, 3, and 4).