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Investigation into the Aberrant Pathways of Hodgkin’s Lymphoma

Curley, Helen (2013) BINP32 20122
Degree Projects in Bioinformatics
Abstract
Abstract

Hodgkin’s lymphoma (HL) is a common lymphoma of the Western world and the therapies used to treat it have considerable side effects. Epstein Barr Virus (EBV) infection is associated with the pathogenesis of HL, though little is known about its contribution. Gene expression studies with microarrays are useful for determining genes and pathways associated with diseases and can be used to identify possible therapeutic targets. Here I report the analysis of several microarray data sets of Hodgkin’s lymphoma and EBV, including the identification of oncogenes, tumour suppressor genes and transcription factors significantly up or down regulated in Hodgkin’s lymphoma and the investigation of the overlap between Hodgkin’s lymphoma... (More)
Abstract

Hodgkin’s lymphoma (HL) is a common lymphoma of the Western world and the therapies used to treat it have considerable side effects. Epstein Barr Virus (EBV) infection is associated with the pathogenesis of HL, though little is known about its contribution. Gene expression studies with microarrays are useful for determining genes and pathways associated with diseases and can be used to identify possible therapeutic targets. Here I report the analysis of several microarray data sets of Hodgkin’s lymphoma and EBV, including the identification of oncogenes, tumour suppressor genes and transcription factors significantly up or down regulated in Hodgkin’s lymphoma and the investigation of the overlap between Hodgkin’s lymphoma associated genes and EBV regulated genes. (Less)
Abstract
Popular science summary

Hodgkin’s lymphoma (HL) is a common B cell lymphoma of the Western world and the therapies used to treat it have considerable side effects. Epstein Barr Virus (EBV) infection is associated with the pathogenesis of HL, though little is known about its contribution. B-lymphocyte undergoes two rounds of differentiation; first in the bone marrow where it becomes a Naïve B cell and a second within the germinal centre (GC) of the lymph nodes. It is here that somatic hypermutation (SHM) occurs and two intermediate GC B cells can be found; centroblasts and centrocytes. The B cells leave the GC as either memory or Plasma B cells. The Ig Variable region is altered during SHM and the distinct patterns found in HRS cells... (More)
Popular science summary

Hodgkin’s lymphoma (HL) is a common B cell lymphoma of the Western world and the therapies used to treat it have considerable side effects. Epstein Barr Virus (EBV) infection is associated with the pathogenesis of HL, though little is known about its contribution. B-lymphocyte undergoes two rounds of differentiation; first in the bone marrow where it becomes a Naïve B cell and a second within the germinal centre (GC) of the lymph nodes. It is here that somatic hypermutation (SHM) occurs and two intermediate GC B cells can be found; centroblasts and centrocytes. The B cells leave the GC as either memory or Plasma B cells. The Ig Variable region is altered during SHM and the distinct patterns found in HRS cells suggest they originate from pre-apoptotic GC B cells.

Gene expression studies with microarrays are useful for determining genes and pathways associated with diseases and can be used to identify possible therapeutic targets. Here, I report the analysis of several microarray datasets of HL and EBV, including the identification of oncogenes, tumour suppressor genes and transcription factors significantly up or down-regulated in HL and the investigation of the overlap between HL associated genes and EBV regulated genes.

By performing Pearson’s correlation coefficient analysis, it was discovered that HRS cells may originate from the B cell that is somewhere between the GC B cells and memory B cells.

The identification of an aberrantly expressed gene lists was completed using Limma analyses of multiple HL datasets and only genes identified as aberrant in both datasets were conserved in the lists. The use of multiple datasets strengthens the reliability of the results. The gene lists created by these analyses were extremely narrowed down but appear to be relevant to the pathogenesis of HL; all genes in the lists had functions that relate to cancer. The aim of the project was to identify a set of genes that are aberrantly expressed in HL and that play a role in the pathogenesis of HL, with a hope of aiding a better understanding of the pathogenesis and possible identification of therapeutic targets.

One particularly interesting gene was identified; BATF3. BATF3 is a transcription factor that is specifically expressed in B cells and due to their high sequence similarity is thought to work similarly to its family member BATF. BATF3 and BATF bind JUN in order to transcribe their common targets. BATF competes with FOS to bind JUN. The FOS:JUN promotes cell lysis in EBV positive cells, but BATF:JUN keep EBV positive cells in latency. The suggestions that BATF3 could be a cell specific control of the lytic switch in EBV, suggests it may be a useful therapeutic target and BATF3 will undergo further experimental investigation.

Advisor: Wenbin Wei
Master´sDegree project 60 credits in Bioinformatics 2013
School of Cancer Sciences, University of Birmingham (Less)
Please use this url to cite or link to this publication:
author
Curley, Helen
supervisor
organization
course
BINP32 20122
year
type
H2 - Master's Degree (Two Years)
subject
language
English
id
4057210
date added to LUP
2013-09-19 16:30:15
date last changed
2013-09-19 16:30:15
@misc{4057210,
  abstract     = {Popular science summary

Hodgkin’s lymphoma (HL) is a common B cell lymphoma of the Western world and the therapies used to treat it have considerable side effects. Epstein Barr Virus (EBV) infection is associated with the pathogenesis of HL, though little is known about its contribution. B-lymphocyte undergoes two rounds of differentiation; first in the bone marrow where it becomes a Naïve B cell and a second within the germinal centre (GC) of the lymph nodes. It is here that somatic hypermutation (SHM) occurs and two intermediate GC B cells can be found; centroblasts and centrocytes. The B cells leave the GC as either memory or Plasma B cells. The Ig Variable region is altered during SHM and the distinct patterns found in HRS cells suggest they originate from pre-apoptotic GC B cells. 

Gene expression studies with microarrays are useful for determining genes and pathways associated with diseases and can be used to identify possible therapeutic targets. Here, I report the analysis of several microarray datasets of HL and EBV, including the identification of oncogenes, tumour suppressor genes and transcription factors significantly up or down-regulated in HL and the investigation of the overlap between HL associated genes and EBV regulated genes. 

By performing Pearson’s correlation coefficient analysis, it was discovered that HRS cells may originate from the B cell that is somewhere between the GC B cells and memory B cells. 

The identification of an aberrantly expressed gene lists was completed using Limma analyses of multiple HL datasets and only genes identified as aberrant in both datasets were conserved in the lists. The use of multiple datasets strengthens the reliability of the results. The gene lists created by these analyses were extremely narrowed down but appear to be relevant to the pathogenesis of HL; all genes in the lists had functions that relate to cancer. The aim of the project was to identify a set of genes that are aberrantly expressed in HL and that play a role in the pathogenesis of HL, with a hope of aiding a better understanding of the pathogenesis and possible identification of therapeutic targets. 

One particularly interesting gene was identified; BATF3. BATF3 is a transcription factor that is specifically expressed in B cells and due to their high sequence similarity is thought to work similarly to its family member BATF. BATF3 and BATF bind JUN in order to transcribe their common targets. BATF competes with FOS to bind JUN. The FOS:JUN promotes cell lysis in EBV positive cells, but BATF:JUN keep EBV positive cells in latency. The suggestions that BATF3 could be a cell specific control of the lytic switch in EBV, suggests it may be a useful therapeutic target and BATF3 will undergo further experimental investigation. 

Advisor: Wenbin Wei
Master´sDegree project 60 credits in Bioinformatics 2013
School of Cancer Sciences, University of Birmingham},
  author       = {Curley, Helen},
  language     = {eng},
  note         = {Student Paper},
  title        = {Investigation into the Aberrant Pathways of Hodgkin’s Lymphoma},
  year         = {2013},
}