Metabolic Vulnerabilities of Acute Myeloid Leukemia Stem Cells

• Applicant: Privatdozent Dr. Simon Raffel
• Subject Area: Hematology, Oncology
• Term: since 2019
• Project identifier: Deutsche Forschungsgemeinschaft (DFG) - Project number 411791825

Acute Myeloid Leukemia (AML) is an aggressive hematological malignancy, which is characterized by the accumulation of clonal myeloid blast cells unable to differentiate into mature cells. Chemotherapy induces remission in the majority of patients but relapse rates are very high and lead to poor clinical outcomes. Relapse and refractoriness are caused by chemotherapy-resistant leukemic stem cells (LSC) and in order to improve patient survival, it is therefore essential to eradicate LSC. The predominant approach to study and target LSC is based on aberrant immunophenotypes of LSC. However, the efficacy of this approach may be limited due to the plasticity of LSC phenotypes. Our work and recent literature suggest that LSC employ characteristic amino acid, energy, and lipid metabolism. Strategies to modulate these very fundamental aspects of cell biology may represent a more comprehensive and effective type of therapy despite LSC surface marker heterogeneity. Hence, a major objective of this proposal is to identify and target metabolic vulnerabilities in LSC. The work program is subdivided into three main aspects: First, we have previously identified that suppression of alpha-ketoglutarate (Alpha KG)-dependent dioxygenases in LSC constitutes a common feature of AML beyond mutations in IDH1/2 and TET2. We will now systematically study and interfere with aKG homeostasis in vitro and in vivo to target LSC populations. Second, LSC populations still consist of thousands of cells and true LSC may be a minority. On single cell level, we will therefore link metabolic properties such as ROS levels, mitochondrial potential and lipid content to transcriptome and function in order to identify metabolic properties and specific vulnerabilities of true LSC. Third, metabolite fingerprints at initial diagnosis, remission and relapse as well as LSC specific metabolite signatures may not only provide a prognostic score that can help to guide therapy decisions for AML patients; it also identifies metabolic pathways and vulnerabilities exploitable for novel therapy approaches. We will therefore apply targeted metabolomics to a large AML patient cohort and LSC populations, and integrate metabolic, mutational and clinical data to pinpoint LSC-specific and clinically relevant metabolic pathways.The experimental approaches converge into efforts to identify targetable metabolic vulnerabilities in LSC by understanding their fundamental biology. Based on the results, novel diagnostic tools and specific therapeutic strategies will be developed and tested in pre-clinical and eventually in early phase clinical settings. Furthermore, important findings as well as experimental platforms will the extended to other hematologic and solid organ cancer entities in the future.

• DFG Programme: Independent Junior Research Groups