WP1 addresses the key challenge to identify disease cells at the earliest possible. The overall goal is to draw a timeline of the steps in the pathogenesis that will enable the In WP1, researchers developed robust model systems, including murine models and specialized cell lines, to understand the pathogenesis of myeloid diseases. They discovered the impact of specific mutations, such as STAG2 and CSNK1A1, on disease progression and therapy resistance. Using primary patient-derived samples and new methods like single-cell RNA sequencing and kinome activity profiling, they elucidated single-cell mechanisms affecting disease progress. Key findings included transcriptional changes and molecular mechanisms underlying STAG2 mutations, the impact of CSNK1A1 mutations on hematopoietic stem and progenitor cells, and the role of mesenchymal stromal cells from CHIP individuals in remodeling the progenitor cell compartment.
In WP2, the focus was on studying epigenetic regulators as potential drug targets for therapeutic intervention, aiming to intercept early disease cells. Researchers used advanced cellular and mouse models, as well as primary cells from MDS patients, to investigate the contribution of epigenetic regulation to MDS pathogenesis. They found that the interplay between progenitor cells and leukemic cells involves cell-specific pathways, with STAG2 playing a key role. They also identified druggable targets using CRISPR-Cas9, modeled the NUP98::KDM5A fusion protein, and tested amiodarone derivatives, finding a compound effective against NUP98::KDM5A-dependent cancer cells. Additionally, they developed methods for precise degradation of NUP98 fusion oncoproteins and identified new NUP98 fusions as potential treatment targets.
In WP3, the goal was to develop novel pre-clinical models and improved data analysis tools to accelerate research progress towards intercepting myeloid diseases. Researchers used 3D models to investigate aging effects, finding that aged-like human bone marrow niches enhance the proliferation and fitness of pre-leukemic MDS cells. They performed extensive genomics analyses on MDS patient samples, identifying novel VEXAS variants and developing methods to deconvolute gene expression profiles. They also optimized a Patient Derived Xenograft model for pre-clinical evaluation of new therapies, identifying potential therapeutic targets, and developed protocols to generate iPSC cells from MDS patient cells. Additionally, they created a bioinformatics pipeline to improve scRNA-Seq data analysis, detecting non-linear gene expression changes and capturing dynamic pathway shifts.
During the program, the ESRs kept on disseminating their results through posters and oral communications at conferences, and especially more actively close to the end of the project. The management team was compromised on following the dissemination strategy described in the section 2.3 of the Description of the Action, facilitating internal communication and maximizing external dissemination. Until today, the scientific WP leaders were closely monitoring the progress of ESRs but they have not identified results that might be exploitable and warrant protection
