SP 1 - LeukoSyStem

Single-cell multi-omic and metabolic characterization of leukemic stem cells to elucidate drivers of pathogenesis and therapy resistance at the single cell level

Acute Myeloid Leukemia (AML) develops through sequential genetic lesions in hematopoietic stem cells (HSCs). For example, preleukemic HSCs (pHSCs) already carry mutations present in AML (e.g., DNMT3A or TET2), but retain their ability to differentiate into healthy blood cells. The acquisition of additional mutations in these cells eventually leads to AML with chemo-resistant leukemia stem cells (LSCs) at the top of a cellular hierarchy. Targeted therapies of LSCs to improve the clinical outcomes of AML patients is an area of active research, but a major challenge remains: LSCs, preleukemic HSCs, healthy HSCs, and leukemia cells lacking stem cell properties (called blasts) are difficult to separate using conventional methods. Only combined genome and transcriptome analyses of individual cells have the potential to clearly distinguish between healthy blood stem cells, pre-leukemic cells and leukemia cells with and without stem cell properties. Together with Dr. Lars Velten (CRG Barcelona, Spain) we will generate and use such single-cell multi-omics datasets to systematically identify LSC-specific markers, biological processes, and potential therapeutic targets. In addition, the cellular metabolism of HSCs, pHSCs, LSCs, and blasts as well as its importance for therapeutic success and resistance development is increasingly becoming the focus of attention.
Therefore, the aim of TP1 is to identify LSC-specific surface markers, genes, pathways and metabolic properties using novel methods of single cell genomics, single cell transcriptomics, single cell metabolism and single cell resistance testing. Identified therapeutic targets and prognostic biomarkers will be functionally validated and in larger patient cohorts.