The role of the reductive stress response as a vulnerability in hematologic malignancies

• Applicant: Dr. Michael Heider
• Subject Area: Hematology, Oncology
• Term: since 2022
• Project identifier: Deutsche Forschungsgemeinschaft (DFG) - Project number 510821888

Redox homeostasis is of critical importance to all living organisms that use oxygen in cellular respiration and is therefore tightly regulated especially in cancer cells such as acute myeloid leukemia (AML). Next to the well characterized oxidative stress pathways, excessive reducing equivalents can perturb cell signaling pathways, change the formation of disulfide bonds and disturb mitochondrial homeostasis. This state triggers the reductive stress response, which has recently been shown to be regulated via the FEM1B-FNIP1 axis. Redox homeostasis, signaling and mitochondrial activity are highly relevant in the initiation, progression and response to treatment in AML. Moreover, publicly available datasets show that FEM1B is overexpressed in AML and high expression of FEM1B correlates with adverse overall survival of AML patients. Assessing the role of the FEM1B-FNIP1 axis and the identification of novel key regulators in the reductive stress response in AML could therefore expose significant vulnerabilities and therapeutic options in this devastating disease. Starting from initial experiments, which will provide insights into the dependency of AML cells on a functional reductive stress response and its regulators FEM1B and FNIP1, an unbiased genome-wide synthetic lethality screen will be conducted in AML cell lines in search for further central modifiers of the reductive stress response. Upon validation of the screen, RNAseq analysis will be used to reveal which pathways are affected by the synthetic lethal hit. The functional characterization and mechanistic understanding of synthetic lethality will then provide the rationale for a combined targeted treatment approach with a FEM1B inhibitor, which can be therapeutically exploited in the context of AML. Finally, the in vitro findings will be corroborated in AML mouse models and primary patient samples. In summary, the proposed project strives to understand how reductive stress signaling and mitochondrial activation are integrated into signaling networks in AML cells and will result in the development of a tumor-specific and effective therapeutic strategy.

• DFG Programme: WBP Fellowship
• International Connection: USA
• Host: Professor Dr. Michael Rape