Student projects
Within several ongoing projects we can use the help of bachelor / master students. See below for more info
POSITIONS AVAILABLE PLEASE CONTACT PROJECT LEADER
FUNCTIONAL STUDIES TO ELUCIDATE THE SUSCEPTIBILITY MECHANISMS OF SNP ALLELES ASSOCIATED WITH SUSCEPTIBILITY ON HODGKIN LYMPHOMA
Keywords: Hodgkin lymphoma, GWAS, SNP, HLA and susceptibility.
Short description of project:
Hodgkin lymphoma (HL) accounts for approximately 30% of all B cell lymphomas in the Western world and is the most common malignancy in young adults. Genome wide association studies (GWAS) have established a clear genetic component with significant associations in the HLA locus and several non-HLA loci.
Interestingly, most associated SNPs map to genomic loci that contain genes that are implicated in key pathways involved in cHL pathogenesis. However, the effects of the SNP alleles on expression and functionality of the nearby genes in relation to cHL susceptibility remain unclear. In this study we try to elucidate the mechanisms underlying the risk and protective effects of the associated SNPs on HL development.
The associations in the HLA region were the strongest and these findings were consistent with previous HLA typing studies. We are currently exploring possible associations with endoplasmic reticulum amino peptidase 1 (ERAP1), a key peptidase involved in HLA class I antigen presentation and with Killer immunoglobulin-like receptors (KIRs), which can recognize certain HLA molecules. The aim of our follow-up studies is to elucidate the susceptibility in HLA-stratified subgroups and to explore the underlying mechanisms.
In addition, SNPs were identified near the transcription factors (TFs) TCF3, GATA3 and REL and in the cytokine IL13. To unravel susceptibility mechanisms of the TFs, we study the effect of the SNP-alleles on mRNA expression levels (eQTL), protein expression levels (pQTL) and on cellular composition (cQTL). The IL13 missense SNP results in two protein variants. These IL13 protein variants will be tested for their effects on STAT6 phosphorylation and HL cell growth.
Student project (technician or master) for 5-10 months
Project leaders (PI): Arjan Diepstra and Anke van den Berg
Contact: a.van.den.berg01@umcg.nl
Understanding the function of the oncogenic MYC-miR150-MYB-ZDHHC11/B network in B cell non-Hodgkin lymphoma
Keywords: Burkitt lymphoma, non-coding RNAs, gene expression, protein expression.
Short description of project:
Previous studies in our lab revealed involvement of a novel oncogenic network in the pathogenesis of Burkitt lymphoma (BL). This network included five distinct components, two protein-coding genes, i.e. MYC and MYB, one microRNA, i.e. miR-150 and two genomic loci encoding protein coding and long noncoding gene loci, i.e. ZDHHC11 and ZDHHC11B. MYC and MYB are transcription factors that are involved in pathogenesis of many cancer subtypes including BL. MiR-150 was found to be one of the MYC-repressed genes, which binds to the 3’-UTR region of the MYB transcript and thereby represses MYB protein expression. Overexpression of miR-150 induced a marked decrease in growth of BL cells. Using GO2-RIP-Chip we identified ZDHHC11 and ZDHHC11B as two novel targets of miR-150. ZDHHC11 and ZDHHC11B encode poorly-studied family members of the palmitoyl transferases. In addition, these loci encode long noncoding RNAs for which the function is largely unknown. All transcripts contain a high number of miR-150 binding sites, suggesting a potential role as miR-150 sponge. The aim of our ongoing studies is to unravel the underlying pathogenetic mechanism and establish the relevance of the network in other types of B cell lymphoma.
To establish the functional relevance of the different gene products of the ZDHHC11 and 11B gene loci, we will perform overexpression and knockdown expression studies to copy and rescue the phenotype observed upon miR-150 overexpression. This will be achieved by using various techniques such as cloning, cell culturing, gene silencing (shRNAs, CRISPR-Cas), viral transfections, GFP competitions assays, FACS, qRT-PCR and Western blotting. We, we try to understand the interplay between the five components, and how the network is involved in the progression of BL.
Student project (technician or master) for 5-10 months
Project leaders (PI): Lotteke Swier and Joost Kluiver
Contact: l.j.y.m.ziel-swier@umcg.nl
NEW TREATMENT TARGETS IN DIFFUSE LARGE B CELL LYMPHOMA
Keywords: BH3 profiling, lymphoma, treatment, mechanism.
Short description of project:
Diffuse large B-cell lymphoma is an aggressive lymphoma in which treatment fails in approximately 40% of patients. Additional treatments are needed. We have re-analyzed the gene expression profiles of more than 1800 DLBCL patients and identified several relevant targets that are involved in different important oncogenic pathways like the DNA damage response, cancer metabolism and immune regulation. These targets need to be evaluated on DLBCL cell lines and patient material to look at the effect on cell viability, apoptosis, induction of DNA damage by themselves as well as in combination with currently used first and second line therapy. Dynamic BH3 profiling will be assessed to study the effect of drug treatment on the dependency of cells on pro and anti-apoptotic proteins and to predict which drugs targeting anti-apoptotic proteins can be combined with the new targets and be successful in the treatment of cancer.
Student project (technician or master) for 5-10 months
Project leaders (PI): Lydia Visser and Tom van Meerten
Contact: l.visser@umcg.nl or t.van.meerten@umcg.nl