Projektbeschreibung
Zur Pathogenese des myelodysplastischen Syndroms: Welche Rolle spielen die Spleißfaktoren?
Das myelodysplastische Syndrom ist eine Gruppe heterogener Erkrankungen, die mit dysfunktionalen Blutzellen einhergehen und häufig in Richtung Leukämie fortschreiten. Das myelodysplastische Syndrom ist durch Mutationen in Genen gekennzeichnet, die am Spleißen der mRNA beteiligt sind, doch der pathogene Mechanismus ist noch weitgehend unklar. Das EU-finanzierte Projekt PATRES-MDS wird der Hypothese nachgehen, dass Mutationen in Spleißfaktorgenen tragende Blutzellen dominieren und die klonale Hämatopoese bei Personen über 70 vorantreiben. Das Forschungsteam wird die Wechselbeziehung des Alterns mit Mutationen in den Genen SF3B1 und SRSF2 untersuchen, welche die Proteine der Spleißmaschinerie kodieren. Diese werden außerdem anhand eines Mausmodells der Krankheit getestet, um im lebenden Organismus weitere Störungen zu finden, die das myelodysplastische Syndrom auslösen.
Ziel
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.
Wissenschaftliches Gebiet
Schlüsselbegriffe
Programm/Programme
Thema/Themen
Finanzierungsplan
ERC-COG - Consolidator GrantGastgebende Einrichtung
CB2 1TN Cambridge
Vereinigtes Königreich