Modeling Marginal Zone Lymphomagenesis - Project Summary
Marginal zone lymphomas (MZL), the second most common subtype of indolent lymphomas, is a B-cell
malignancy where the tumor microenvironment plays an important role in its pathogenesis. Furthermore, it lacks
reliable preclinical models including cell lines, which has hampered rational drug development for this common
indolent lymphoid tumor. The phosphoinositide 3-kinase (PI3K), protein kinase B (Akt), mammalian target of
rapamycin (mTOR) pathway is one of the frequently deregulated pathways in human cancer and is an essential
component of the B-cell receptor signaling pathway that is important to the pathogenesis of B-cell malignancies.
Interestingly, PI3K/AKT/mTOR (PAM) pathway inhibitors such as copanlisib and capivasertib have shown strong
clinical activity in patients with relapsed or refractory MZL. The tumor suppressor gene (TSG) phosphatase and
tensin homolog (PTEN) negatively regulate PI3K signaling, while the TSG liver kinase B1 (LKB1), also known
as STK11 negatively regulates mTOR signaling. Prior studies using heterozygous global knockout of PTEN and
hypomorphic mutation that decreases LKB1 expression in genetically engineered mouse model (GEMM) lead to
formation of indolent lymphomas that were not well characterized, in addition to other types of malignancies such
as pheochromocytomas, prostate, breast and pancreatic carcinomas. Therefore, we have generated novel
GEMM where we have restricted the activation of the PAM pathway to B cells using the Cre/loxP system with
CD19-Cre in order to create a more cell type-specific tumor model and more accurately mimic the underlying
human disease, with the long-term goal of using these models for evaluating targeted and immunotherapies for
human MZL. We will test the following hypotheses: Aim 1: To study the impact of PI3K/AKT/mTOR pathway
activation in the development of marginal zone lymphomas (MZL) using novel genetically engineered
mice. Aim 2: To determine the optimal drug combination for targeting the PI3K/AKT/mTOR pathway in
MZL. These studies will be the first to demonstrate the possibility of modeling human MZL in mice, using a model
with a functional immune system. This novel model will have a tremendous impact on our understanding of the
underlying biology of the disease and on our ability to design future rationale therapies for this incurable
malignancy.
