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Molecular analysis of myelodysplastic syndrome iPSC and iPSC-derived disease relevant cell types

Alternative title: null

Awarded: NOK 5.9 mill.

Myelodysplastic syndromes (MDS) are a group of blood disorders characterized by inefficient blood formation. Patients suffering from MDS accumulate immature blood cells in the bone marrow and have reduced numbers of functional, mature cells in their peripheral blood. Approximately 25% of MDS patients progress to acute myeloid leukemia (AML), which significantly reduces the life expectancy. One of the major challenges of today´s healthcare is to understand the molecular cause for the onset and progression of a disease and to provide personalized therapy to efficiently cure a malignancy in a patient-specific manner. Patient samples are a valuable resource to develop such approaches, but limited amounts can be isolated from each patient and therefore do not allow multifactorial analyses. This is, however, often necessary to understand the complexity of the disease. We overcome this limitation by generating patient-derived cells (so called induced pluripotent stem cells (iPSC)) that can be expanded to cell numbers that allow multiple experiments and to study a disease in the dish. The aim of our study is to use patient-derived iPSC to discover yet unidentified causes of MDS that can eventually be used to identify novel biomarkers to improve diagnostics and/or treatment. When investigating signaling defects in iPSC we generated from MDS samples, we found several proteins important for chromatin compaction to be dysregulated. Very little is known about how these proteins regulate blood development, and we therefore generated the first genome-wide chromatin interaction map in healthy donor blood cells for lamin B1 and lamin B receptor. In addition, we generated such maps for MDS samples in order to compare how dysregulation of these proteins changes the interaction with chromatin. Interestingly, we also found a signaling pathway that seems to influence the efficiency of somatic cell reprogramming. The latter would be relevant to better understand which pathways are important mediators of somatic cell reprogramming, and may help to improve the general efficiency of generating iPSC. This in turn can enable access to samples or cell types that reprogram less efficiently than skin fibroblasts.

Somatic cell types such as skin fibroblasts can be reprogrammed to induced pluripotent stem cells (iPSC) by ectopic expression of four transcription factors Oct4, Klf4, Sox2 and c-Myc thereby offering great opportunities to generate patient-specific cells that can be maintained and expanded into disease-relevant cell types and be studied in the dish. We have recently demonstrated that pluripotency can also be induced in peripheral blood cells, enabling us to access disorders where the mutation is restrict ed to blood cells, for instance blood malignancies. Blood cancers account for approximately 7% of cancers worldwide, and occur in all age groups including children and adolescents. The amounts of cells that can be obtained from patients or from blood samp les already stored at biobanks are often of limited use for extensive experimental procedures since these cell numbers do not permit multifactorial analysis. Our proposal focuses on the generation of iPSC to study myelodysplastic syndromes (MDS), a clonal hematopoietic disorder in the age group above 50 that is characterized by impaired blood cell differentiation and a predisposition to transformation to acute myeloid leukemia (AML). Primary patient samples, MDS-iPSC and MDS-iPSC derived disease-relevant cell types will be analyzed in order to identify underlying molecular causes of MDS pathogenesis with the ultimate goal to detect novel biomarkers and drug targets that may be used for diagnostic and in therapy.

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