Acute myeloid leukaemia (AML) is the most common acute leukaemia in adults. It is a haematological malignancy arising from the occurrence of genetic mutations in clonal hematopoietic progenitors, which cause a block in differentiation and an uncontrolled growth of leukemic blasts in the bone marrow. Beside direct targeting the leukemic cells other approaches aim to identify and target common features within this complex disease. One potential target is the bone marrow microenvironment, which is the site where leukemic cells arise, expand, and eventually develop resistance to therapy. It is constituted out of different types of cells, e.g. mesenchymal stromal cells (MSCs), with a predominant vascular component responsible for nutrient and metabolite turnover, the ingress and egress of different cells, and the regulation of normal hematopoietic stem and progenitor cell (HSPC) function. Thus far, comprehensive analyses of the molecular and metabolic changes in AML BM MSCs of larger patient cohorts are sparse.
Therefore, we will apply our expertise on MSC biology for investigations of metabolic changes in distinct types of AML, such as MLL- and NPM1c-AML. Our collaboration partner at King’s, Prof. Eric So, will analyse molecular mechanisms of chemoresistance and leukemic stem cell activity in these AML subtypes using single cell multi-omics approaches.
We will analyse serial samples (diagnosis/remission/relapse) from 5 to 10 MLL-AML and NPM1c-AML patients. The samples and the respective clinical data are collected within the scope of the AML registry of the German-wide “Study Alliance for Leukaemia” (www.sal-aml.org) coordinated in Dresden. While the cellular heterogeneity and key molecular features of AML cells will be analyzed by our King’s partner, Professor So, the stromal fraction will firstly directly be analyzed at the Metabolomics-Platform of the NCT and processed for RNA sequencing, and secondly MSCs will be further cultured and analysed.
The overall goal is a better prediction of treatment response of distinct AML cases and therefore potentially a more host- and disease-specific therapeutic intervention.