MEK inhibition in RAS-mutated/EZH2-inactivated CMML

Chronic myelomonocytic leukemia (CMML) is an aggressive hematopoietic neoplasia frequently driven by aberrations modifying the RAS oncogenes (RASmut). Unfortunately, current therapeutic approaches for RASmut CMML patients are insufficient. In preliminary data of this project, we demonstrate that RASmut in CMML often co-occur with specific epigenetic alterations and that this co-occurrence influences the leukemogenic potential of RASmut. Cell culture data suggest that this mutational co-occurrence might cause a preferential sensitivity to pharmacological RAS-signaling inhibitors. In this project, we will follow up on these data and perform an extensive preclinical evaluation of this novel therapeutic approach. We will, therefore, use specific Rasmut mouse models of CMML with and without the co-occurrence of this epigenetic lesion. We will use these animals to test for the efficacy and toxicity of a series of RAS-signaling inhibitors. To strengthen the translational aspect, we will further validate these data in ex-vivo experiments using CMML patient specimens carrying these molecular aberrations. Finally, we will transplant these human samples into immunocompromised mice and use these models as an additional treatment validation phase. Ultimately, we will employ novel sequencing and transcriptomic methods to elaborate on the mechanisms behind preferential sensitivity to RAS-signaling inhibitors in these models. In conclusion, the data generated in this project will preclinically test a novel therapeutic approach for CMML patients carrying RASmut together with epigenetic lesions. Besides testing its feasibility, efficacy, and toxicities, the project will also aim to elaborate on the mechanisms behind this pharmacological strategy. Ultimately, we will use the data generated within this project to pave the way to initiating a respective clinical trial.