Multi-scale, single-cell systems biology of leukemia stem cells in pathogenesis and therapy
Acute Myeloid Leukemia (AML) is an aggressive blood cancer characterized by the accumulation of immature and functionless blood cells (leukemic blasts) in the bone marrow. These leukemic blasts are constantly produced by a small number of leukemic stem cells (LSCs) capable of initiating and sustaining the disease. LSCs originate from normal blood-forming (hematopoietic) stem cells by the accumulation of genetic abnormalities (mutations). Disease eradication and long-term cure require treatment courses that eliminate LSCs. In addition to genetic abnormalities, metabolic properties, the bone marrow microenvironment, and the immune system play important roles in the pathogenesis of AML.
Conventional technologies are unable to distinguish between healthy and leukemic stem cells and cannot adequately represent the complex molecular and cellular characteristics of the disease. By applying novel single cell analysis methods to AML patient samples, we will provide a systematic characterization of both pathogenesis and therapy-resistance mechanisms. For this purpose, we will identify surface markers, genes and metabolic properties with specificity for LSCs by means of single cell genomics, single cell transcriptomics, single cell metabolism and single cell resistance testing (TP1). In addition, we will characterize the AML microenvironment in the bone marrow niche using single-cell and spatially-resolved analysis methods (TP2). We will develop novel, computer-assisted methods for integrating the various single-cell MultiOmics data from TP1 and TP2 (TP3), thus gaining a systemic understanding of the interaction of multiple factors in the development and therapy resistance of AML. The findings will be used as a starting point for the development of biomarkers and new therapeutic approaches with the aim of improving the prognosis of patients with AML.
Press release DKFZ/EMBL/University Hospital Heidelberg about LeukoSyStem: €2.45 m to investigate leukaemia causes and therapies