Studier av fibrosutveckling vid barnleukemi i en humaniserad benmärgsmodell

Acute lymphoblastic leukemia (ALL) is the most common pediatric leukemia and is effectively treated using modern treatment protocols. However, failure to respond to therapy occurs, indicating a bad prognosis. Bone marrow (BM) fibrosis is frequently observed in ALL and is likely to affect treatment response. However, the mechanisms that cause fibrosis are not understood. We will therefore investigate ALL fibrosis using a humanized BM fibrosis
xenotransplantation model.

We have developed immunofluorescence (IF) multiplexing combined with RNAscope technology and could show that leukemic blasts and megakaryocytes in pediatric ALL expressed high levels of fibrosis-inducing factors (TGFB, PDGF). We have also developed the first humanized BM fibrosis model, which we will use to investigate ALL fibrosis pathogenesis and leukemia-induced BM alterations.

We will use combined IF/RNAscope staining to investigate expression of fibrosis-related genes in pediatric ALL. Human BM (ossicles) will be generated by s.c. implantation of BM stromal cells in NSG mice. BM fibrosis will then be induced by transplantation of leukemic cells and evaluated by histopathology. The role of specific factors on fibrosis will be investigated using gene manipulation strategies. Leukemia-induced hematopoietic/microenvironmental aberrations and fibrosis targets will be identified using single cell sequencing technologies (sc-RNAseq, CITE-seq) combined with spatial analysis (scanning microscopy, DSP). Drugs/molecules with anti-fibrotic activity will be tested in the fibrosis ossicle model.

We expect that our experiments will help to identify the mechanisms of BM fibrosis in leukemia which will allow to develop novel stroma-targeting therapies that have the potential to further improve current ALL treatment.