Quantifying the dynamic evolution from myelodysplastic syndrome to acute myeloid leukemia

• Applicant: Dr. Verena Körber
• Subject Area: Bioinformatics and Theoretical Biology
• Term: since 2023
• Project identifier: Deutsche Forschungsgemeinschaft (DFG) - Project number 526169089

Myelodysplastic syndrome (MDS) is an acquired bone marrow failure with high risk of progression to acute myeloid leukemia (AML). At present, early and reliable risk stratification of MDS patients remains a formidable challenge. Here, I propose to quantitatively study the somatic evolution from a normal blood cell to leukemia, with the overall objective of developing prognostic models for individual patients or patient subgroups. In a first step, I will characterize the genetic evolution in a unique cohort of 12 MDS patients with, and without progression to AML. Based on deep whole genome sequencing data of serial bone marrow samples, I will infer the clonal topology and its temporal changes for each patient. In a second step, I will develop dynamic models of clonal evolution that are based on established principles from population genetics and describe the growth and extinction of (pre-)malignant clones along with mutation accumulation in the tissue. By parametrizing these models with the clonal phylogenies inferred in step 1, I will estimate the time-scale of driver mutation acquisition and clonal selection on the level of individuals. In this way, I will generate personalized models of disease progression. By comparing parameter estimates between patients, I will search for candidates of prognostic markers. Moreover, I will date back the origin of the disease and of clones emerging during malignant growth, to provide guidance for diagnostic intervals and treatment decisions. I will validate this approach on independent whole genome sequencing data from >100 MDS and AML samples, taken at a single time point for each patient, and correlate the model predictions with clinical outcome. In sum, I aim to comprehensively characterize the evolutionary dynamics driving progression form MDS to AML, which may aid early diagnosis and risk stratification in MDS patients and healthy individuals.

• DFG Programme: WBP Fellowship
• International Connection: United Kingdom
• Host: Professor Paresh Vyas, Ph.D.