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

• Final Report Year: 2024

Final Report Abstract

The microenvironment has an essential role in the disease mechanisms of myelodysplastic syndromes (MDS), a heterogenous disease that causes clonal expansion of mutated hematopoietic stem cells (HSPCs) and eventually leads to acute myeloid leukemia. Within the bone marrow stroma niche, mesenchymal stromal cells (MSCs) are reprogrammed by mutated HSPCs to favor their expansion. Since the molecular mechanisms behind this crosstalk are not yet fully understood, this project aimed to uncover epigenetic regulators in MSCs crucial for disease development. Using powerful genetic screening tools, I wanted to uncover chromatin regulators in MSCs that represent attractive targets for leukemia interception. Moreover, I wanted to understand how the surface proteome of MSCs changes after contact with mutated HSCP clones to shed further light on the microenvironment in leukemia. The targeting of the bone marrow niche is an innovative therapeutic approach that has great potential to yield novel drug targets. Taken together, my goal was to improve our understanding of disease mechanisms in MDS.

Publications

• Understanding and reverting the reprogramming of bone marrow stroma cells in MDS. Poster presentation. Quantitative dynamics of aging and premalignancy conference, IRB, Barcelona, Spain.
  Dias E., Winkler R., Diesch J., Malinverni R., Corujo D., Bech-Serra J.J., de la Torre C., Van der Garde M., Götze K.S., Sdelci S. & Buschbeck M.
  
• Targeting the bone marrow stroma niche as a therapeutic approach for myeloid malignancies. Poster presentation. Stem Cell Niche conference, Copenhagen, Denmark.
  Winkler R., Dias E., Bech-Serra J.J., Medyouf H., Götze K.S., de la Torre C. & Buschbeck M.
  
• Increased peritoneal B1-like cells during acute phase of human septic peritonitis. iScience, 27(7), 110133.
  von Loeffelholz, Christian; Winkler, René; Weigel, Cynthia; Piskor, Eva-Maria; Vivas, Wolfgang; Rauchfuß, Falk; Settmacher, Utz; Rubio, Ignacio; Weis, Sebastian; Gräler, Markus H.; Bauer, Michael & Kosan, Christian