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The "SALL programme": Stem cells, Ageing, Leukemia and Lymphoma (SALL)

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​​​​​​​​​​​​​​​​​​​​The research programme ‘Stem cells, Ageing, Leukemia and Lymphoma’ program (SALL) performs research on basic, translational and clinical science. Its mission is to better understand the molecular mechanisms regulating hematopoietic stem cell functionality, how these are perturbed in the development of leukemia and lymphoma, and how this can be translated into improvement of treatment and late sequelae of these diseases.  SALL is embedded in the Cancer Research Center Groningen (CRCG) of the UMCG and has close ties with the GSMS to train the future generation of scientists.

Mission  

The ‘Stem cells, Ageing, Leukemia and Lymphoma’ programme (SALL) performs research on basic, translational and clinical science. The mission of SALL is to better understand the molecular mechanisms regulating hematopoietic stem cell functionality, how these are perturbed in the development of leukemia and lymphoma, and how this can be translated into improvement of treatment and late sequelae of these diseases.

Programme Leaders   Principal Investigators   Description of the Programme  

The aim of the SALL program is to study fundamental and clinical aspects of stem cells, leukemia and lymphoma by incorporating various disciplines with state-of-the-art technologies and -omics approaches. The focus comprises the full range of basal, applied, translational and clinical research topics. The weekly meetings provide an excellent learning environment for PhD students and facilitate interactions between clinicians and basic scientists with different backgrounds. The PIs and other members of the SALL program are appointed at various departments, i.e. Hematology, Pathology & Medical Biology, Pediatric Oncology, Cell Biology and the European Institute for the Biology of Ageing (ERIBA). The aim is to cover the entire spectrum “from bench to bed”. This is achieved by the broad range of expertise of the PIs, from clinical to translational and fundamental topics, resulting in a multidisciplinary research group.

The stem cell research lines focus on how blood cell development is regulated during normal hematopoiesis, and during ageing. Most studies are aimed at identifying mechanisms and genes that specify hematopoietic stem cell self-renewal, using the mouse as a model system. Also, the flatworm is used as a model to understand the fundamental mechanisms underlying regulation of stem cell activity during ageing, and human stem cells (hematopoietic and otherwise) are studied in detail as well. Stem cell purification, transplantation, genetic perturbation, transcriptional profiling and epigenetic screenings are key instruments in these studies.

The leukemia research lines have a clear focus on leukemic stem cells and leukemia development in children and adults. Primary human hematopoietic stem/progenitor cells and leukemic cells from patients are manipulated by a variety of cell biological and molecular techniques to deepen the insights in the development of human leukemia. One of the aims is to identify leukemia-specific plasma membrane markers using transcriptomics and proteomics in order to detect, target and ultimately eradicate leukemic stem cells. Another topic is to investigate how normal young and old stem cells are affected by intervention of chemotherapy and transplantation, and via which mechanisms the process of ageing contributes to the development of hematological malignancies. Finally, there is a focus on how alterations in the microenvironment and angiogenesis are linked to leukemic progression and resistance. The results of all these studies are translated into clinical studies.

The lymphoma research lines focus on the most common B-cell lymphoma types and aim to deepen the insight into the pathogenetic mechanisms of lymphoid malignancies. The research topics include genetic aberrations and susceptibility, interaction between the tumor cell and its microenvironment, serological biomarkers and on the role of non-coding RNAs. Another aspect studied is how ageing of the immune system, and especially of the B-cell compartment, contributes to development of specific B-cell lymphoma subtypes. These B-cells most likely escape from apoptosis due to accumulation of genetic and epigenetic aberrations over time. Results from these fundamental studies are translated into clinical studies such as testing their value as diagnostic criteria for classification, using biomarkers for treatment response and prognostication and late treatment-related toxicity. These studies are conducted in close collaboration with the (inter)national working parties for lymphoma and leukemia within HOVON and EORTC.

Relevance to Healthy Ageing  

Ageing is an important determinant in hematological malignancies, and with our continuously ageing societies the need for better treatment options for these diseases continuous to increase. Appropriate functioning of the immune system is essential for healthy ageing. Stem cell renewal and differentiation play crucial roles in this process. Ageing affects stem cell self-renewal and may result in enhanced or reduced stem cell renewal capacity. Accumulation of genetic and epigenetic aberrations in time may lead to the formation of leukemic stem cells and the subsequent development of leukemia. Studying stem cell renewal and leukemic stem cell renewal will reveal the mechanisms that lead to inappropriate functioning and leukemia.

Lymphomas develop from B or T lymphocytes that escape from apoptosis due to accumulation of genetic and epigenetic aberrations over time. Thus, ageing is also a crucial factor in lymphoma development. Of interest in this respect is that some lymphoma subtypes occur both in young and elderly individuals, whereas other lymphomas are specific for either young or old individuals. In general age is an important prognostic factor. Unravelling the genetic and epigenetic aberrations in lymphoma will increase our insight in the pathogenetic processes and will help to improve current treatment regimens, predict prognosis and response to therapy.

The activities of the SALL programme are centered on these aspects, and also include basic ageing animal models, which will contribute to our understanding of stem cell biology and thereby help to improve classification, prognostication and therapeutic choices for all hemato-oncological patients.

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