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MEK inhibition in RAS-mutated/EZH2-inactivated CMML
- Abstract
- Wider research context/theoretical framework:
Chronic myelomonocytic leukemia (CMML) is an aggressive hematopoietic neoplasia and is frequently driven by aberrations modifying the RAS oncogenes (RASmut). Unfortunately, current therapeutic approaches for RASmut CMML patients are insufficient. We demonstrate that RASmut in CMML often co-occur with inactivating aberrations of the epigenetic modifier EZH2 (EZH2inact). In-vitro cell culture studies reveal that RASmut/EZH2inact myeloid cells exhibit RAS-signaling hyperactivation and might be preferentially sensitive to RAS-MAPK/ERK inhibition with MEK inhibitors (MEKi).
Hypotheses/research questions/objectives:
Research question:
We ask whether distinctive pharmacological approaches can therapeutically target RASmut/EZH2inact CMML.
Hypothesis:
We hypothesize that RASmut and EZH2inact synergistically activate RAS-signaling pathways in CMML and confer increased sensitivity to MEKi.
Objectives:
By strategically incorporating our biobank with clinically well-annotated patient specimens into state-of-the-art in-vitro and in-vivo approaches, we will initially extend our knowledge on the effects of RASmut/EZH2inact co-occurrence on RAS-MAPK/ERK signaling in CMML. We will then analyze MEKi therapy within these models and ask for preferential sensitivity in the RASmut/EZH2inact genotype. Ultimately, we will assess the effects of MEKi on RASmut/EZH2inact CMML-leukemic stem cells (LSC) and clonal evolution.
Approach/methods:
We will initially elaborate on the effects of EZH2inact on the activation of RASmut-signaling in transgenic murine in-vivo models, primary CMML patient specimens, and patient-derived xenografts (PDX). These analyses will include the flow-cytometry-based assessment of RAS-signaling in hematopoietic stem and progenitor cells (HSPC) and LSC. We will then use these models to assess the effects of RASmut/EZH2inact co-occurrence on MEKi. Ultimately, we will aim to assess the therapeutic potential of MEKi to cure RASmut/EZH2inact CMML. Therefore, we will study the effects of MEKi treatment on RASmut/EZH2inact HSPC compartments, CMML-LSC and clonal evolution of CMML.
Level of originality/innovation
Targeting aberrant RAS signaling has been a significant focus of research for the last decades. Despite the recent advent of direct next-generation RAS inhibitors, the therapeutic benefit for RASmut CMML patients was limited. This project assesses a novel approach and proposes that successful molecular-guided treatment in RASmut CMML must consider the influence of co-existing and functionally interacting lesions.
Primary researchers involved
Armin Zebisch has a strong track record on RAS-signaling in myeloid neoplasms and will be the principal investigator. He will be supported by clinical hematologists and basic researchers with profound expertise in CMML and the models used within this project. A PhD student and technician will further support his lab team in executing this project.
- Keywords
- Chronisch myelomonozytäre Leukämie
- EZH2
- RAS-signaling
- Project Leader:
- Zebisch Armin
- Duration:
- 01.01.2025-31.12.2028
- Programme:
- Einzelprojekt
- Type of Research
- basic research
- Staff
- Zebisch, Armin, Project Leader
- Lind, Karin, Co-worker
- Perfler, Bianca, Co-worker
- Gruden, Eva, Co-worker
- MUG Research Units
- Division of Haematology
- Division of Pharmacology