Targeting phospholipid metabolism of chemotherapy-resistant leukemic stem cells

• Applicant: Privatdozent Dr. Simon Raffel
• Subject Area: Hematology, Oncology
• Term: since 2022
• Project identifier: Deutsche Forschungsgemeinschaft (DFG) - Project number 508064562

Chemotherapy-resistant leukemia stem cells (LSCs) drive relapse and refractoriness in acute myeloid leukemia (AML). In order to improve patient survival, it is therefore essential to target LSCs. Our recent proteomics analysis of LSCs and healthy human hematopoietic stem and progenitor cells (HSPCs) reveals that LSCs employ a characteristic phospholipid metabolism and express high levels of the acyltransferase MBOAT7, a member of the Lands’ cycle controlling arachidonic acid-containing phosphatidylinositol species. Phosphatidylinositols are constituents of biological membranes and affect cell function by serving as second messengers and as precursors for prostaglandins and other lipid mediators. We hypothesize that MBOAT7-driven remodeling of (i) arachidonic acid and its derivatives and (ii) phosphatidylinositol and closely related phosphatidylinositol phosphates contributes to stemness of leukemic cells and thus drives therapy resistance in AML. Within the proposed project, we plan to study the function of primary patient-derived LSCs upon manipulation of MBOAT7 in vitro and in vivo (objective 1), elucidate its mechanism of action by multi-omics and lipid tracing experiments (objective 2), validate our findings in larger cohorts of matched diagnostic and relapse samples and determine synergism of MBOAT7 knockdown and conventional chemotherapeutic agents (objective 3).

• DFG Programme: Research Grants