Abstract 4634: Mouse model for nodal marginal zone lymphoma
Authors: Yazbeck Victor , McConnell Ian , Lownik Joseph , Sindel Ariel , Sabo Roy , Chesney Alden , Lai Guanhua , Mauro Adolfo , Zweit Jamal , Martin Rebecca , Conrad Daniel , Grant Steven , Windle Jolene , Grossman Steven 
Published: August 2019

Abstract
Introduction: Indolent B-Cell Non-Hodgkin’s Lymphoma (i-NHL) represents a heterogeneous group of lymphoproliferative malignancies, encompassing 40% of NHL, that remains largely incurable. The B-cell receptor signaling pathway is activated in B-cell malignancy and mediates its activity mainly through the Phosphoinositide 3-kinase (PI3K) pathway. Furthermore, novel PI3K inhibitors, such as idelalisib and copanlisib, have shown impressive clinical activity in several indolent lymphomas including marginal zone lymphoma (MZL). This further supports the important role of the PI3K pathway in these tumors.
Methods We generated a genetically engineered mouse model carrying heterozygous knockout alleles of both the tumor suppressor genes Phosphatase and Tensin Homolog (PTEN) and Liver Kinase B1 (LKB1), leading to over-activation of the PI3K-mTOR pathway in all mouse tissues. We closely monitored these mice for tumor formation by at least weekly physical examinations for several months. Upon tumor detection, tumor size was recorded weekly using calipers, with an experimental endpoint of 15-20mm in any dimension. One half of the tumor was immediately preserved in a 4% paraformaldehyde solution and prepared for sectioning, H&E and immunohistochemical staining.
Results: Thirty mice died or were sacrificed due to disease progression, defined as either lymph node enlargement and/or splenomegaly. All mice showed either abnormal lymphadenopathy or splenomegaly. By Kaplan-Meier analysis, we saw a steady decrease in both tumor-free and overall survival after 3 months of age. Utilizing the product limit method, the median survival time was 6 months (95% CI: 6, 8). A total of 51 lymph nodes were sent for IHC and pathological identification. Of the 51 nodes, 61.5% (N=32) showed indolent Non-Hodgkin’s Lymphoma, 25% (N=13) were atypical, and 11.5% (N=6) were reactive. All lymph nodes with indolent NHL were Marginal Zone subtype. In order to generate a more specific model of B cells, we used the Cre/LoxP system with CD19-Cre. We detected an increase in the average portion of MZL B cells in the spleen of the homozygous mice compared to wild type (38.3% vs 4.9%, p=0.0216).
Conclusion: Nodal marginal zone lymphoma remains an incurable indolent lymphoma that lacks preclinical models. As novel agents become available, it is important to have a better understanding of the underlying pathogenesis of this malignancy and be able to model it in an immunocompetent mouse with a preserved microenvironment. Our data provides, for the first time, a proof of concept on the role of the PI3K-mTOR pathway in the pathogenesis of nodal marginal zone lymphoma and paves the way for future studies understanding the biology of this disease, and developing rational therapies for this incurable malignancy.
Note: This abstract was not presented at the meeting.
Citation Format: Victor Yazbeck, Ian McConnell, Joseph Lownik, Ariel Sindel, Roy Sabo, Alden Chesney, Guanhua Lai, Adolfo Mauro, Jamal Zweit, Rebecca Martin, Daniel Conrad, Steven Grant, Jolene Windle, Steven Grossman. Mouse model for nodal marginal zone lymphoma [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2019; 2019 Mar 29-Apr 3; Atlanta, GA. Philadelphia (PA): AACR; Cancer Res 2019;79(13 Suppl):Abstract nr 4634.