Mechanistic models of leukemia-niche interaction using multimodal single cell profiling

ongoing

The bone marrow is one of the most dynamic adult stem cell niches containing hematopoietic stem cells and non-hematopoietic mesenchymal stem and stromal cells, which make up the bone marrow niche. The niche regulates the immune system and constitutes a major determinant of chemoresistance in hematological malignancies, including acute myeloid leukemia (AML). Identifying the mechanisms by which AML interacts with its niche will open novel therapeutic avenues. AML is driven and maintained by leukemic stem cells (LSCs), and failure to eradicate them will result in relapsing of the disease. Yet, despite decades of research on LSCs, none of the therapies aiming at eradicating them reached clinical practice. Recent studies suggest an important role for bone marrow stromal and immune cells in driving AML. Together with our preliminary data, that show LSCs-induced upregulation of metastasis-related genes in stromal cells, this leads to the hypothesis that AML remodels its niche in ways that favours its survival and represses healthy hematopoiesis. Most studies in AML focus on LSC-intrinsic, stromal niche, or immune mediated mechanisms separately. Thus, we currently lack a comprehensive view of the complexity of the human bone marrow and its interaction with AML. To close these gaps, we propose an ambitious experimental design including multi-modal single cell sequencing of an AML cohort followed by innovative computational approaches integrating these data into predictive cell-type specific models - to generate mechanistic hypotheses about AML-niche interactions that we then test using patient-derived xenograft and in vitro culture models. Our ambitious project will provide fundamental insights into stem cell-niche interactions and may lead to a paradigm-shift in treating hematological malignancies - away from eradicating malignant cells towards reconstituting a healthy niche that generates a healthy immune environment.