Description du projet
Le rôle des facteurs d’épissage dans la pathogenèse des syndromes myélodysplasiques
Les syndromes myélodysplasiques (SMD) forment un groupe hétérogène de troubles associés au dysfonctionnement des cellules sanguines, et progressant souvent vers la leucémie. Les SMD se caractérisent par des mutations des gènes impliqués dans l’épissage de l’ARNm, mais leur mécanisme pathogène reste flou. Le projet PATRES-MDS, financé par l’UE, compte étudier l’hypothèse selon laquelle les cellules sanguines porteuses de mutations des gènes de facteur d’épissage gouvernent et entraînent l’hématopoïèse clonale chez les personnes âgées de plus de 70 ans. Les chercheurs étudieront les interactions entre le vieillissement et les mutations des gènes SF3B1 et SRSF2 qui codent les protéines du phénomène d’épissage. Ces interactions seront également testées dans un modèle murin de la maladie afin d’identifier d’autres perturbations in vivo susceptibles de favoriser les SMD.
Objectif
The myelodysplastic syndromes (MDS) are a heterogeneous group of malignancies of the haematopoietic stem cell (HSC) with a tendency for leukaemic transformation. Despite some new therapies, the MDS are lethal to most sufferers and in need of new effective treatments. Splicing factor gene mutations are the commonest class of somatic alterations in MDS and primarily affect the genes SF3B1, SRSF2, U2AF1 and ZRSR2. The mutations are associated with altered mRNA splicing, but each affects different transcripts and it is unclear how they drive MDS. It has been hypothesised that different mutations share pathogenetic mechanisms, distinct from their effects on alternative splicing. Recently, augmented R-Loop formation leading to cell cycle arrest of haematopoietic progenitors was identified as one such mechanism. However, we have no understanding of how the mutations drive clonal HSC expansion, a critical node for the development of new treatments. To this end, we and others described the phenomenon of clonal haematopoiesis (CH), widely held as the precursor of MDS and other myeloid cancers. We observed CH driven by splicing gene mutations only in individuals aged ≥ 70-years-old. This and other observations point to an interaction between ageing and the ability of splice factor mutations to drive clonal expansion. Here, I propose to investigate the two most common variants in MDS, SF3B1-K700E and SRSF2-P95H.
Research Plan
1. Characterise the global impact of the mutations using state-of-the-art transcriptomics and proteomics
2. Use bone marrow samples from elderly humans to study the interaction of ageing with splicing factor mutations
3. Generate mosaic mutant mice to investigate the impact of ageing and other perturbations on SF3B1-K700E and SRSF2-P95H haematopoiesis
Findings will be validated and pursued mechanistically to derive new insights into the molecular mechanisms and interaction of the mutations with ageing, whilst also identifying new candidate therapies.
Champ scientifique
Mots‑clés
Programme(s)
Régime de financement
ERC-COG - Consolidator GrantInstitution d’accueil
CB2 1TN Cambridge
Royaume-Uni