The SMURF2-YY1-C-MYC Axis in the Germinal Center Reaction and Diffuse Large B Cell Lymphoma: A Dissertation
Authors
Trabucco, Sally E.Faculty Advisor
Hong Zhang, PhDAcademic Program
Cell BiologyUMass Chan Affiliations
PediatricsDocument Type
Doctoral DissertationPublication Date
2016-06-27Keywords
Dissertations, UMMSLymphoma, Large B-Cell, Diffuse
YY1 Transcription Factor
Ubiquitin-Protein Ligases
Germinal Center
Proto-Oncogene Proteins c-myc
Diffuse Large B-Cell Lymphoma
YY1 Transcription Factor
Ubiquitin-Protein Ligases
Germinal Center
Proto-Oncogene Proteins c-myc
SMURF2-YY1-C-MYC Axis
Cancer Biology
Cell Biology
Neoplasms
Metadata
Show full item recordAbstract
Diffuse large B cell lymphoma (DLBCL) is the most common non-Hodgkin’s lymphoma. Patients who fail conventional therapy (~50%) have a poor prognosis and few treatment options. It is essential to understand the underlying biological processes, the progression of the disease, and utilize this information to develop new therapeutics. DLBCL patients with high C-MYC expression have a poor prognosis and new therapeutics for these patients are needed. This thesis describes work testing the hypothesis that JQ1, which can indirectly inhibit C-MYC in some tumors, can be used as an effective treatment for DLBCL. Some tumors have an unknown mechanism causing high C-MYC expression, leading me to investigate the underlying mechanisms. YY1 is a transcriptional regulator of c- Myc and has been implicated in DLBCL and as a potential regulator of the germinal center (GC) reaction. DLBCL arises from GC cells or post-GC cells. I tested the hypothesis that YY1 regulates the GC reaction. SMURF2 is an E3-ubiquitin ligase for YY1 and a tumor suppressor for DLBCL. I was interested in examining the mechanism underlying the suppression of DLBCL by SMURF2 leading to the hypothesis that SMURF2 regulates the GC. This thesis shows JQ1 leads to cell death and cellular senescence in human DLBCL cells. I conclude that BRD4 inhibition by JQ1 or derivatives could provide a new therapeutic avenue for DLBCL patients. I also show loss of YY1 perturbs the GC by decreasing the dark zone and increasing apoptosis. Finally I show modulation of SMURF2 does not affect the GC, suggesting SMURF2 utilizes a different mechanism to act as a tumor suppressor and may not modulate YY1 in the context of the GC.DOI
10.13028/M2JP4HPermanent Link to this Item
http://hdl.handle.net/20.500.14038/32239Rights
Copyright is held by the author, with all rights reserved.ae974a485f413a2113503eed53cd6c53
10.13028/M2JP4H