VACANCY: we are looking for a motivated technician on a project focussing on the epigenome of leukemic stem cells.
For info, please contact JJ Schuringa (firstname.lastname@example.org, 0031-50-3619391)
We invite biology, biochemistry and medical students, as well as trainees from the school for laboratory personnel (HLO) to apply for a traineeship.
please contact j.j.schuringa umcg.nl
possible current MSc student projects:
Title: Using the plasma membrane proteome to dissect clonal heterogeneity and track disease progression in Acute Myeloid Leukemia
Hematological malignancies such as leukemia remain very difficult to treat. This is likely related to the clonal complexity of leukemias. Multiple clones can co-exist in individual patients, and since these subclones carry distinct combinations of mutations in their DNA, they most likely require specific drugs or therapeutic approaches. A current challenge in the field is that clonal heterogeneity is revealed by sequencing technologies that do not allow the prospective isolation of these subclones as viable cell populations. The availability of such technologies is essential to be able to study the molecular characteristics of genetically distinct subclones such as their transcriptome, proteome and epigenome, as well as their specific drug sensitivities. By performing extensive quantitative proteome studies we have been able to identify and validate novel plasma membrane proteins that are specific for leukemic cells, and even allow the identification of distinct subclones. Within the current project, we will functionally study these subclones in detail in order to understand molecular mechanisms underlying leukemic transformation and develop novel treatment strategies.
Title: Combining transcriptome, quantitative proteome and metabolome approaches to identify targetable vulnerabilities in AML.
Depending on their cellular quiescent and active states, metabolic signatures controlling the energy production of hematopoietic stem cells (HSCs) differ. A thorough understanding of the regulation of these signatures at the molecular level is still lacking. We generated transcriptome, quantitative proteome and LC-MS/MS-based or NMR-based metabolome data in normal and leukemic human HSCs and developed an integrative approach in order to link genetic differences with metabolomics. Thus, we have identified differences in metabolic routing between normal and leukemic stem cells. We are currently investigating what the molecular basis is for these differences in metabolic routing. In other words: what would explain the Warburg effect in leukemic cells at the molecular level? Also, we are evaluating whether these metabolic differences can be exploited in order to further improve treatment strategies for patients with leukemia.
Title: Hematopoietic stem cells do not live alone: what about their niche?
Hematopoietic stem cells do not live alone, but reside in bone marrow niches where they are surrounded by various other cells types such as mesenchymal stromal cells, adipocytes, osteoblasts, endothelial cells and even neural cells. The bone marrow is also relatively hypoxic, with important molecular and cellbiological consequences such as stabilization of HIF transcription factors and a shift from oxidative phosphorylation towards glycolysis, but also various other processes that are still poorly understood. The fate of HSCs is critically dependent on signals they receive from this niche and direct interactions they have with various of these cell types within the bone marrow. In order to truly understand the biology of stem cells, a detailed insight into these processes is needed. We have developed in vitro and in vivo tools in which we reconstruct the 2D/3D bone marrow niche in our experimental setup. By using shRNA/CRISP technologies we can genetically modify either the HSCs themselves or the niche in order to functionally study these interactions.
Title: Cellular stress-induced remodeling of the epigenetic landscape
Cells are constantly exposed to various kinds of genotoxic and propeotoxic stress. We have recently discovered that various types of cellular stress (i.e. heat shock) induce a release of epigenetic regulatory Polycomb complexes from the chromatin. Polycomb complexes have previously been shown to be essential for proper regulation of self-renewal of both normal hematopoietic stem cells and leukemic stem cells, and are frequently deregulated in cancer. Our data suggests that Polycomb-mediated epigenetic regulation is altered upon exposure to cellular stress. This research project focusses on (i) the molecular mechanisms driving Polycomb complex release upon cellular stress and (ii) the long-term effects of cellular stress on the epigenome.
Title: Molecular role of PRC1.1 in leukemic stem cells
We recently identified the non-canonical PRC1.1 complex as an essential complex for leukemic stem cell viability (Van den Boom et al., 2016, Cell Reports). In contrast to canonical Polycomb complexes that are known to silence their target genes, we unexpectedly found that the PRC1.1 complex binds to the transcription start sites of actively transcribed metabolic genes. In addition, depletion of PRC1.1 components interfered with leukemogenesis both in vitro and in vivo using xenograft mouse models. This project focusses on the molecular role of the PRC1.1 complex in leukemic cells. We will study the consequences of PRC1.1 depletion on the epigenome and will investigate how PRC1.1 contributed to activation of its target genes.
email: j.j.schuringa umcg.nl
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