Graduation Date

Spring 5-4-2019

Document Type

Dissertation

Degree Name

Doctor of Philosophy (PhD)

Programs

Pathology & Microbiology

First Advisor

Kai Fu

Abstract

Aggressive B-cell lymphomas are diverse group of neoplasms that arise at different stages of B-cell development and by various mechanisms of neoplastic transformation. Aggressive B-cell lymphomas include many types, subtypes and variants of diffuse large B-cell lymphoma (DLBCL), Burkitt lymphoma (BL), mantle cell lymphoma (MCL) and B lymphoblastic lymphoma. The treatment of patients with aggressive B-cell lymphomas remains a clinical challenge. Conventional chemotherapeutic regimens, mainly based on the CHOP (cyclophosphamide, hydroxydaunorubicin, oncovin and prednisone) combination, obtain a relatively high number of complete or partial clinical responses (20-80%), but the tumor relapses in most patients, who will die of the disease. Addition of rituximab, a chimeric monoclonal antibody directed against CD20, to this combination increases the overall survival, and the response rate and duration. However, different clinical evolution suggests that not all patients need the same therapy.

Rac1, a small guanosine triphosphatase (GTPase), has been found to be dysregulated in many human malignancies, including solid tumors and chronic myeloid leukemia. However, its status in MCL remains unknown. Here, we found Rac1 is overexpressed at both mRNA and protein levels in MCL cell lines and cases, and over-expression is correlated with poor prognosis. Functional study showed that inhibiting Rac1 by shRNA or specific inhibitor NSC 23766 significantly inhibited cell viability and enhanced chemotherapy drug Adriamycin-induced cytotoxic effect in MCL cells. Mechanistic studies showed diminished activity of several oncogenic pathways (AKT/mTOR, NF-κB and ERK) upon Rac1 inhibition. However, as a GTPase, Rac1 is hard to target. Group I P21-associated kinases (PAKs) are well known downstream of Rac1. Here, we demonstrated overexpressed and highly activated Pak2 signaling in MCL, and in DLBCL and BL as well. Inhibition of Pak2, not Pak1, by siRNA or inhibitor FRAX 597 significantly inhibited lymphoma cells viability, through diminishing activity of AKT/mTOR and NF-κB pathways, which furtherly confirmed the pro-survival role of Rac1-Pak2 axis in lymphoma situation. Synergistic effect between FRAX 597 and Adriamycin or ibrutinib was shown in MCL. Moreover, FRAX 597 could overcome the ibrutinib resistant in MCL and ABC-DLBCL. Collectively, studies suggest targeting Rac1-Pak2 as a promising strategy in clinical treatment of aggressive B-cell lymphomas.

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