PhD Project "Targeting phospholipid metabolism of chemotherapy-resistant leukemic stem cells" (Raffel 2023-01) - Heidelberg University

Date: 01/03/2023

Application Deadline: 31/01/2023

Our work directly links metabolic changes to long-term reorganization of chromatin activity in leukemic stem cells

Acute Myeloid Leukemia (AML) is an aggressive hematologic malignancy with poor overall survival (Dohner et al, 2015). While classic chemotherapy regimens lead to remission in the majority of patients, relapse rates are very high. Relapse and therapy resistance are caused by the hierarchical organization of AML with a minor fraction of leukemic stem cells (LSCs) at the apex generating leukemic progeny, which make up the majority of leukemic cells. The cancer stem cell model implies that in order to eradicate the disease and achieve long-term remissions, treatment courses must eliminate the LSC population. There is increasing evidence that LSCs harbor specific metabolic properties (Raffel et al., 2017; Jones et al, 2018, Sancho et al., 2016). We have shown that branched chain amino acid (BCAA) metabolism is essential for stemness in LSCs. Mechanistically, branched-chain amino acid transaminase 1 (BCAT1) regulates intracellular alpha-ketoglutarate (aKG) levels. aKG controls the activity of the tumor suppressor protein TET2, which modulates the DNA methylome of leukemic stem cells. Our work directly links metabolic changes to long-term reorganization of chromatin activity in leukemic stem cells (Raffel et al., 2017). 

Our recent proteomics analysis of LSCs and healthy human hematopoietic stem and progenitor cells (HSPCs) revealed 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 (Raffel et al, 2020). 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, elucidate its mechanism of action by multi-omics and lipid tracing experiments, validate our findings in larger cohorts of matched diagnostic and relapse samples and determine synergism of MBOAT7 knockdown and conventional chemotherapeutic agents.

Personal qualifications:

We are looking for a highly motivated PhD student with a background in molecular cell biology and a strong interest in metabolomics – basic expertise in bioinformatics would be a plus. You will become a member of the Raffel lab (https://www.klinikum.uni-heidelberg.de/kliniken-institute/kliniken/zentrum-fuer-innere-medizin-krehl-klinik/innere-medizin-v-haematologie-onkologie-und-rheumatologie/forschung/emmy-noether-ag-raffel) 
at Heidelberg University Hospital, Department of Hematology, Oncology and Rheumatology (Director: Prof. Dr. C. Müller-Tidow). You will participate in the Blood Club and the Heidelberg Leukemia Network (HeLeNe) that connects hematology labs across the Heidelberg. In addition, you will closely interact with our collaboration partners at DKFZ, HI-STEM, EMBL and BZH. All this will provide you with the opportunity to acquire expertise in cutting-edge molecular stem cell, cancer and translational research.

Please submit your application exclusively through the HBIGS application system:

http://www.hbigs.uni-heidelberg.de/main_application.html

Please read more under "Open PhD Positions" on: http://www.hbigs.uni-heidelberg.de