Flt3-ITD signaling-dependent mutational synergies in chromatin remodeling and oncogenic transcription in acute myeloid leukemia maintenance and plasticity

• Applicant: Dr. Jens Schrezenmeier
• Subject Area: Hematology, Oncology ; General Genetics and Functional Genome Biology
• Term: since 2024
• Project identifier: Deutsche Forschungsgemeinschaft (DFG) - Project number 534961357

Acute myeloid leukemia (AML) is an aggressive malignant disease of the bone marrow. Only approximately 30 percent of patients diagnosed with the disease can be cured from it. Relevant advances in the understanding of genetic changes found in AML cells led to significant improvements in available therapeutics in recent years. The plasticity of AML cells and resistance to novel treatments remains a major clinical problem. Still a large proportion of patients suffer from relapses under the current treatment regimes. Therefore a better molecular understanding of AML for improving current therapies is necessary. The first goal of my project is the investigation of co-operative mechanisms of the most frequent genetic lesions in AML (NPM1, FLT3, DNMT3A) on changes in the epigenetic make-up and DNA topology that lead to the malignant phenotype of AML cells in my model systems. For this purpose I will use state-of-the-art high-throughput sequencing methodologies and sophisticated bioinformatic data analysis approaches for integrating the large resulting datasets. From these investigations I will generate a high resolution map of epigenetic and DNA topology changes resulting from the investigated mutational synergies. In a second step I will look at the co-mutation specific epigenetic and DNA topology changes under the inhibition with the novel, clinically highly relevant AML drug and FLT3 inhibitor, quizartinib in my model systems. This is of high clinical relevance as most patients respond initially well to current treatment approaches with FLT3 inhibitors but a majority of patients suffer from relapse of resistant leukemia cells. Finally I will use a combination of single-cell sequencing methods coupled with a functional genetic screening to investigate leukemia specific vulnerabilities found in the first two work packages. This approach will be used to characterize mutation and resistance specific changes to find novel treatment approaches for overcoming resistance and relapse of AML cells.

• DFG Programme: WBP Fellowship
• International Connection: United Kingdom
• Host: Professor Dr. Brian Huntly