ORCID ID

0000-0002-8384-6217

Graduation Date

Fall 12-20-2019

Document Type

Dissertation

Degree Name

Doctor of Philosophy (PhD)

Programs

Pathology & Microbiology

First Advisor

Javeed Iqbal, Ph.D.

Abstract

Peripheral T-cell lymphoma (PTCL) is a group of complex clinicopathological entities associated with an aggressive clinical course. Angioimmunoblastic T-cell lymphoma (AITL) and PTCL-not otherwise specified (PTCL-NOS) are the two most frequent categories accounting for more than 50% of PTCLs. Gene expression profiling (GEP) defined molecular signatures for AITL and delineated biological and prognostic subgroups within PTCL-NOS (PTCL-GATA3 and PTCL-TBX21). Genomic copy number analysis and targeted sequencing revealed unique genomic abnormalities and oncogenic pathways, indicating distinct oncogenic evolution. PTCL-GATA3 exhibited higher genomic complexity characterized by frequent loss or mutation of tumor suppressor genes targeting the CDKN2A/B-TP53 axis and PTEN-PI3K pathways. PTCL-TBX21 had fewer abnormalities, primarily targeting cytotoxic effector genes, and was enriched in mutations of genes regulating DNA methylation. AITL showed lower genomic complexity compared to other PTCL entities, suggesting it is epigenetically driven, yet frequent co-occurring gains of chromosome 5 and 21 were observed. Thus, to further explore the underlying pathobiology of AITL, we established an AITL-like murine model. We have found TET2 to be the most recurrent mutation in AITL with evidence that it may be a founder mutation. The generated murine model had a loss of Tet2 in CD4+ T-cells, resulting in the long-term development of an aggressive T-cell lymphoma with a TFH phenotype, similar to AITL. These mice developed lymphomas characterized by massive splenomegaly, marked generalized lymphadenopathy, hepatomegaly and occasional involvement of other parenchymal organs. Serial RNA-sequencing analysis of the pre-neoplastic and neoplastic CD4+ T-cells revealed increased PI3K-AKT signaling and decreased Foxo1 signaling likely mediated through ICOS in the neoplastic cells, promoting TFH cell expansion. Overall, we demonstrated that novel GEP-defined PTCL subgroups likely evolve by distinct genetic pathways and that AITL is driven more by epigenetic alterations, such as loss of Tet2 as it resulted in an aggressive T-cell lymphoma with a TFH phenotype. These findings emphasize the critical need for genetically faithful model systems for studying these common PTCL entities in order to improve therapeutic options.

Available for download on Saturday, October 23, 2021

Share

COinS