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Dissertation/Thesis Abstract

STAT3 Promotes Aggressive Tumorigenesis in Diffuse Large B Cell Lymphoma
by Hardee, Jennifer Marion, Ph.D., Yale University, 2012, 131; 3535398
Abstract (Summary)

The signal transducer and activator of transcription 3 (STAT3) is a key signal transducer that regulates gene expression in response to a wide array of extracellular signals. It plays a critical role in the regulation of many cellular processes, especially those related to cell growth and apoptosis. For this reason, disregulation of STAT3 signaling causes it to become a powerful oncogene. One of the many cancers in which STAT3 overexpression is found is diffuse large B cell lymphoma (DLBCL). DLBCL is the most common form of lymphoma in the United States, and it is also among the most aggressive. Research into the underlying genetic causes of DLBCL revealed that this disease can be divided into two major subtypes: germinal center B-cell-like (GCB) and activated B-cell-like (ABC). ABC DLBCL responds much more poorly to current treatments.

Recent genotyping studies show that STAT3 is often overexpressed and overactive in this more aggressive subtype. Although previous studies have identified important STAT3 target genes, our understanding of its targets is far from complete, especially in cases where its regulation is abnormal. To investigate how STAT3 might contribute to the aggressive and treatment-resistant phenotype of ABC DLBCL, I have performed genome-wide studies of STAT3 DNA binding using chromatin immunoprecipitation followed by next-generation DNA sequencing (ChIP-Seq) and combined this information with genome-wide gene expression profiling performed using RNA-sequencing (RNA-Seq). Together, these global data sets reveal which loci change their transcription levels in response to increased STAT3 binding in ABC DLBCL.

Using ChIP-seq in patient-derived DLBCL cell lines representing either the GCB or ABC subtype, I have found that STAT3 occupies over 10,000 binding sites throughout the genome. Approximately one third of these demonstrate STAT3 binding and occupancy in one subtype, but not in the other. Additionally, comparative RNA-Seq gene expression profiling found that six percent of the transcriptome is differentially expressed between GCB and ABC DLBCL. This is primarily due to novel genes becoming active in the ABC subtype. Combining the ChIP-Seq binding region information with the RNA-Seq transcriptome data revealed that differential STAT3 binding sites are present near almost a third of all genes that change expression between GCB and ABC DLBCL, leaving little doubt that it is a major regulator of the aggressive clinical phenotype and drug resistance displayed by the ABC subtype. These results provide novel insights into the genetics of oncogenesis in the ABC form of diffuse large B cell lymphoma and shed light onto genes downstream of STAT3 that may contribute to this disease state.

Indexing (document details)
Advisor: Snyder, Michael P.
Commitee: Stein, Elke, Stern, David, Weissman, Sherman
School: Yale University
Department: Molecular, Cellular, and Developmental Biology
School Location: United States -- Connecticut
Source: DAI-B 74/05(E), Dissertation Abstracts International
Subjects: Genetics, Cellular biology, Oncology
Keywords: Aggressive tumorigenesis, DLBCL, Diffuse large B cells, Lymphoma, STAT3
Publication Number: 3535398
ISBN: 978-1-267-85678-4
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