Project description
Insight into the pathogenesis of MDS: the role of splicing factors
Myelodysplastic syndrome (MDS) is a heterogeneous group of disorders that is associated with dysfunctional blood cells and often progresses to leukaemia. MDS is characterised by mutations in genes implicated in mRNA splicing, but the pathogenic mechanism is unclear. The EU-funded PATRES-MDS project will investigate the hypothesis that blood cells carrying mutations in splicing factor genes dominate and drive clonal haematopoiesis in individuals over 70 years of age. Researchers will study the interaction of ageing with mutations in SF3B1 and SRSF2 genes which encode proteins of the splicing machinery. These will also be tested in a mouse model of the disease to identify further in vivo perturbations that drive MDS.
Objective
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.
Fields of science (EuroSciVoc)
CORDIS classifies projects with EuroSciVoc, a multilingual taxonomy of fields of science, through a semi-automatic process based on NLP techniques. See: The European Science Vocabulary.
CORDIS classifies projects with EuroSciVoc, a multilingual taxonomy of fields of science, through a semi-automatic process based on NLP techniques. See: The European Science Vocabulary.
- natural sciences biological sciences biochemistry biomolecules proteins proteomics
- natural sciences biological sciences genetics mutation
- medical and health sciences clinical medicine oncology
You need to log in or register to use this function
We are sorry... an unexpected error occurred during execution.
You need to be authenticated. Your session might have expired.
Thank you for your feedback. You will soon receive an email to confirm the submission. If you have selected to be notified about the reporting status, you will also be contacted when the reporting status will change.
Programme(s)
Multi-annual funding programmes that define the EU’s priorities for research and innovation.
Multi-annual funding programmes that define the EU’s priorities for research and innovation.
-
H2020-EU.1.1. - EXCELLENT SCIENCE - European Research Council (ERC)
MAIN PROGRAMME
See all projects funded under this programme
Topic(s)
Calls for proposals are divided into topics. A topic defines a specific subject or area for which applicants can submit proposals. The description of a topic comprises its specific scope and the expected impact of the funded project.
Calls for proposals are divided into topics. A topic defines a specific subject or area for which applicants can submit proposals. The description of a topic comprises its specific scope and the expected impact of the funded project.
Funding Scheme
Funding scheme (or “Type of Action”) inside a programme with common features. It specifies: the scope of what is funded; the reimbursement rate; specific evaluation criteria to qualify for funding; and the use of simplified forms of costs like lump sums.
Funding scheme (or “Type of Action”) inside a programme with common features. It specifies: the scope of what is funded; the reimbursement rate; specific evaluation criteria to qualify for funding; and the use of simplified forms of costs like lump sums.
ERC-COG - Consolidator Grant
See all projects funded under this funding scheme
Call for proposal
Procedure for inviting applicants to submit project proposals, with the aim of receiving EU funding.
Procedure for inviting applicants to submit project proposals, with the aim of receiving EU funding.
(opens in new window) ERC-2018-COG
See all projects funded under this callHost institution
Net EU financial contribution. The sum of money that the participant receives, deducted by the EU contribution to its linked third party. It considers the distribution of the EU financial contribution between direct beneficiaries of the project and other types of participants, like third-party participants.
CB2 1TN CAMBRIDGE
United Kingdom
The total costs incurred by this organisation to participate in the project, including direct and indirect costs. This amount is a subset of the overall project budget.