Project description DEENESFRITPL Shedding light on leukaemic stem cells as disease drivers Leukaemic stem cells (LSCs) are a low-frequency population of leukaemia cells that give rise to leukaemia and are usually resistant to chemotherapy. As a result, LSCs are considered responsible for disease relapse after therapy. Funded by the Marie Skłodowska-Curie Actions programme, the MRDAML project aims to delineate the phenotype and function of LSCs at presentation as well as during therapy and relapse. Researchers will undertake transcriptomic, genetic and epigenetic analysis of LSCs from patients at different disease stages and identify key players in LSC survival and resistance. Project results will improve current understanding of acute myeloid leukaemia and serve as the foundation for the future design of specific treatments. Show the project objective Hide the project objective Objective Acute myeloid leukemia (AML) is one of the most aggressive and deadliest cancers with frequent relapse. Although initial therapies eliminate most AML blast cells, rare cells with leukemic stem cell (LSC) activity can persist and likely generate minimal residual disease (MRD) to re-initiate AML. Thus, targeting resistant LSCs during MRD might provide a unique opportunity to prolong remission and prevent relapse. However, because it is notoriously challenging to identify rare LSCs present within the vast number of normal blood cells during MRD, the phenotype, plasticity, function and mechanisms of LSCs in resistance and relapse remains poorly understood.Previous study from the Trumpp laboratory demonstrated a convergent pathway via hypermethylationn to drive initiation and progression of AML with IDH mutations or BCAT1 overexpression. However, the common and distinct mechanisms driving resistance in the two AML subtypes has not been explored, despite the observation that BCAT1 expression is upregulated in LSCs and upon relapse.Thus, in this proposal, I will first perform systematic phenotypic characterization of IDHmut/BCAT1hi AML cells to develop a high-quality LSC enrichment strategy. Subsequently, I will combine cutting edge single-cell multi-omics technologies to deeply characterize the mutational, transcriptomic and epigenetic dynamics of individual LSCs at diagnosis, MRD-positive remission and relapse. State of the art analytical methods will be used to integrate these data to dissect IDHmut/BCAT1hi AML with unprecedented resolution, examine the contribution of LSCs in MRD, and identify molecular regulators mediating LSC survival and resistance. Functional validation using pharmacological intervention, genomic editing in cell lines and patient-derived xenograft models will be performed to uncover causal relationships of the identified regulators. Overall, this work will lead to better mechanistic insight of MRD and therapy resistance in IDHmut/BCAT1hi AML. Fields of science medical and health sciencesmedical biotechnologycells technologiesstem cellsnatural sciencesbiological sciencesgeneticsmutationmedical and health sciencesclinical medicineoncologyleukemia Programme(s) HORIZON.1.2 - Marie Skłodowska-Curie Actions (MSCA) Main Programme Topic(s) HORIZON-MSCA-2021-PF-01-01 - MSCA Postdoctoral Fellowships 2021 Call for proposal HORIZON-MSCA-2021-PF-01 See other projects for this call Funding Scheme HORIZON-AG-UN - HORIZON Unit Grant Coordinator DEUTSCHES KREBSFORSCHUNGSZENTRUM HEIDELBERG Net EU contribution € 173 847,36 Address Im neuenheimer feld 280 69120 Heidelberg Germany See on map Region Baden-Württemberg Karlsruhe Heidelberg, Stadtkreis Activity type Research Organisations Links Contact the organisation Opens in new window Website Opens in new window Participation in EU R&I programmes Opens in new window HORIZON collaboration network Opens in new window EU contribution No data
