Exploring epigenetic modulation in bone marrow stroma as novel therapeutic approach to prevent leukaemia

• Applicant: Dr. René Winkler
• Subject Area: Hematology, Oncology ; Immunology ; Cell Biology
• Term: from 2022 to 2024
• Project identifier: Deutsche Forschungsgemeinschaft (DFG) - Project number 498523371

Blood cancers like leukemia are life-threatening diseases which originate from different blood cells and rapidly disseminate in the human body. Acute myeloid leukemia frequently develops from a precursor state, termed myelodysplastic syndrome. It takes several months until the pre-leukemic state of myelodysplastic syndrome evolves into a full-blown so-called secondary leukemia. This time window creates an opportunity for targeting pre-cancerous cells in the bone marrow niche of these patients with innovative treatment options. However, current treatment options for myelodysplastic syndrome are limited. Pharmacological reversion of alterations in the bone marrow microenvironment is expected to have therapeutic benefit by increasing the proliferation and maintenance of healthy hematopoietic stem and progenitor cells and preventing the expansion of mutated stem cell clones. Given the epigenetic nature of the change in stroma cells in the bone marrow, I hypothesize that mining the chromatin regulatory space will allow to identify novel drug targets to reverse the pathophysiological alterations in stroma cells and provide a new therapeutic avenue for the treatment of myelodysplastic syndrome and the prevention of leukemia. As starting point, I will screen a close to comprehensive collection of chromatin regulators using state-of-the-art techniques in stroma cells. Then, I will assess the functional role of top scoring hits from the screen in stroma cell-hematopoietic stem cell crosstalk by using established co-culture systems. Thereby, I aim to evaluate if targeting these epigenetic regulators might restore the dysfunctional bone marrow niche in myelodysplastic syndrome. I expect that my results will improve our understanding of leukemia biology and potentially identify new drug targets for an innovative therapeutic approach based on the epigenetic reprogramming of the bone marrow niche.

• DFG Programme: WBP Fellowship
• International Connection: Spain
• Host: Dr. Marcus Buschbeck