SP 2 - LeukoSyStem

Systemic mapping of the leukemia stem cell microenvironment by combined single-cell and spatial transcriptomics

Acute myeloid leukemia develops through a step-wise accumulation of genetic abnormalities (mutations) in healthy blood-forming (hematopoietic) stem cells. In recent years, it has become apparent that in addition to genetic abnormalities, the bone marrow microenvironment plays a fundamental role in controlling the initiation, progression and relapse of the disease. In particular, cells of the immune system have the ability to specifically recognize, inhibit and eliminate leukemia cells. However, leukemia cells may evade immunity and reprogram the bone marrow into an immune suppressive environment. Reverting this immune suppressive state or specifically targeting immune cells to leukemic cells is the central idea of novel immune therapy approaches. However, the complex interplay of immune and leukemia cells in the bone marrow remains poorly understood. In addition to immune cells, blood vessels, neural cells, as well as a diverse set of poorly described mesenchymal stromal cells have been directly or indirectly implicated in leukemia pathogenesis. Technical limitations have so far impeded a comprehensive and systemic understanding of molecular, cellular and immunological processes associated with leukemia initiation, progression and relapse in patients. In this subproject, we are employing single-cell and spatially-resolved technologies that permit the molecular characterization and localization of all cell types in the bone marrow that might potentially impact on the development of AML. This includes the in-depth analyses of immune cells and rare stromal cell populations. Overall, these analyses will provide a personalized and system-oriented understanding of the interplay between leukemia cells and the microenvironment in AML and finally aim at identifying prognostic biomarkers that can inform treatment choice.

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