Periodic Reporting for period 4 - PATRES-MDS (Pathogenesis and treatment of splicing factor mutant myelodysplastic syndromes)
Reporting period: 2023-11-01 to 2025-04-30
The myelodysplastic syndromes (MDS) are a group of haematological malignancies that affect 5 per 100,000 people each year. The annual incidence of MDS rises with age reaching 30 per 100,000 for those aged 70 years or older. Unfortunately, despite the development of some new treatments, the MDS remain lethal to the majority of sufferers. The only potentially curative treatment for MDS is blood stem cell transplantation (also known as bone marrow transplantation), but this toxic therapy is appropriate only for a small minority of patients. Therefore, the MDS represent an important unmet clinical need and the development of new effective and non-toxic treatments is urgently required. An improved understanding of how and why the MDS develop can help develop effective new treatments. Like all cancers, the MDS are driven by specific DNA gene mutations in blood-making cells (also known as blood stem cells). It is widely accepted that these mutations give a growth advantage to the host cells, however the nature and biological basis of this advantage remain elusive. The most common type of MDS-driver mutations affect genes involved in a process called RNA splicing, a necessary step for the production of mature RNA in cells. Such mutations usually affect the SF3B1 and SRSF2 genes, are found in more than two thirds of MDS cases and are usually responsible for initiating the process of MDS development. In fact, splicing gene mutations can be found in the blood for several years before MDS develop, and drive expansion of the mutant cells specifically in older people for reasons that remain unknown. Notably, as the proportion of people surviving to advanced old age increases, so does the incidence of MDS. The overall objectives of this project are to decipher how mutations in splicing genes SF3B1 and SRSF2 lead to clonal expansion and the development of MDS in older age, and how potential new treatments can reverse the effects of these mutations or eliminate the cells carrying them. We anticipate that our studies will help the development of improved treatments for patients with MDS that will prolong their life and/or cure them from these diseases.
Conclusions of the action
Despite difficulties and delays imposed by the COVID-19 pandemic, the project succeeded in its overall objectives of this project are to decipher how mutations in splicing genes SF3B1 and SRSF2 lead to clonal expansion and the development of MDS in older age, and how potential new treatments can reverse the effects of these mutations or eliminate the cells carrying them. Specifically, we revealed the following: i) We discovered that MDS-associated splicing factor (SF) gene mutations facilitate clonal expansion of mutant cells by corrupting telomere maintenance (see: McLoughlin et al, Nature Genetics 2025). Targeting this effect of SF gene mutations is a candidate therapeutic approach against these cancers. ii) Separately, we discovered that mitochondrial metabolism is a therapeutic vulnerability of SF3B1-mutant MDS and identified specific genes/proteins whose inhibition results in reduced mutant cell growth.
Conclusions of the action
Despite difficulties and delays imposed by the COVID-19 pandemic, the project succeeded in its overall objectives of this project are to decipher how mutations in splicing genes SF3B1 and SRSF2 lead to clonal expansion and the development of MDS in older age, and how potential new treatments can reverse the effects of these mutations or eliminate the cells carrying them. Specifically, we revealed the following: i) We discovered that MDS-associated splicing factor (SF) gene mutations facilitate clonal expansion of mutant cells by corrupting telomere maintenance (see: McLoughlin et al, Nature Genetics 2025). Targeting this effect of SF gene mutations is a candidate therapeutic approach against these cancers. ii) Separately, we discovered that mitochondrial metabolism is a therapeutic vulnerability of SF3B1-mutant MDS and identified specific genes/proteins whose inhibition results in reduced mutant cell growth.
Since the start of this project in May 2019 we generated the tools, protocols, reagents and models that enabled us to pursue our objectives. These included the following:
1. Using state-of-the-art genome editing, we have introduced MDS-associated mutations in splicing genes in blood cell lines and are now using these for downstream studies to determine the effects of these mutations on blood cells
2. We generated two new mouse models and have started using these to study the mutations in vivo, in a way that closely mimics what happens in humans with MDS and obviates the need for (unphysiological) haematopoietic stem and progenitor cell (HSPC) transplantation.
3. We tested pro-inflammatory treatments to mimic ageing-related inflammation in mice repopulated with cells carrying normal and Sf3b1-mutant cells.
4. We obtained ethical approval and systematically collected samples from patient volunteers at Cambridge University Hospitals. Samples obtained were used in experimental studies and were instrumental in the two key discoveries of the project pertaining to telomere biology and mitochondrial metabolism.
5. By analysis of UK Biobank data, we identified that SF-mutant MDS and clonal haematopoiesis (CH) arise significantly more commonly in individuals that inherited shorter telomeres.
6. By analysing paired proteomics and transcriptomics/RNA splicing data we discovered that mitochondrial metabolism is a vulnerability of SF3B1-mutant blood cells. In depth studies revealed that targeting specific mitochondrial genes has a detrimental effect on the growth of SF-mutant cells and should be investigated as a therapeutic strategy against SF-mutant MDS or SF-mutant CH.
Overview of the results
Our work has made two important new discoveries that gave new insights into the pathogenesis of SF-mutant MDS and their precursor, SF-mutant CH. First that splicing factor (SF) gene mutations drive clonal expansion of mutant cells by corrupting telomere maintenance (McLoughlin et al, Nature Genetics 2025). Second that mitochondrial metabolism is a therapeutic vulnerability of SF3B1-mutamnt MDS and that inhibition of specific genes/proteins inhibited mutant cell growth. Going forward, we will continue to investigate the molecular basis of these observations and work to develop therapeutic approaches for patients with SF-mutant MDS and CH. We anticipate that these findings will lead directly to therapeutic advances that will improve the survival and quality of life of patients with SF-mutant MDS and potentially also help to prevent the development of these cancers.
1. Using state-of-the-art genome editing, we have introduced MDS-associated mutations in splicing genes in blood cell lines and are now using these for downstream studies to determine the effects of these mutations on blood cells
2. We generated two new mouse models and have started using these to study the mutations in vivo, in a way that closely mimics what happens in humans with MDS and obviates the need for (unphysiological) haematopoietic stem and progenitor cell (HSPC) transplantation.
3. We tested pro-inflammatory treatments to mimic ageing-related inflammation in mice repopulated with cells carrying normal and Sf3b1-mutant cells.
4. We obtained ethical approval and systematically collected samples from patient volunteers at Cambridge University Hospitals. Samples obtained were used in experimental studies and were instrumental in the two key discoveries of the project pertaining to telomere biology and mitochondrial metabolism.
5. By analysis of UK Biobank data, we identified that SF-mutant MDS and clonal haematopoiesis (CH) arise significantly more commonly in individuals that inherited shorter telomeres.
6. By analysing paired proteomics and transcriptomics/RNA splicing data we discovered that mitochondrial metabolism is a vulnerability of SF3B1-mutant blood cells. In depth studies revealed that targeting specific mitochondrial genes has a detrimental effect on the growth of SF-mutant cells and should be investigated as a therapeutic strategy against SF-mutant MDS or SF-mutant CH.
Overview of the results
Our work has made two important new discoveries that gave new insights into the pathogenesis of SF-mutant MDS and their precursor, SF-mutant CH. First that splicing factor (SF) gene mutations drive clonal expansion of mutant cells by corrupting telomere maintenance (McLoughlin et al, Nature Genetics 2025). Second that mitochondrial metabolism is a therapeutic vulnerability of SF3B1-mutamnt MDS and that inhibition of specific genes/proteins inhibited mutant cell growth. Going forward, we will continue to investigate the molecular basis of these observations and work to develop therapeutic approaches for patients with SF-mutant MDS and CH. We anticipate that these findings will lead directly to therapeutic advances that will improve the survival and quality of life of patients with SF-mutant MDS and potentially also help to prevent the development of these cancers.
The progress made by our project, PATRES-MDS has led directly to the discovery of novel mechanisms and therapeutic vulnerabilities of SF-mutant MDS that were previously entirely unforeseeable and that go beyond the state of the art. We are optimistic that they will translate into new therapeutic advances in the treatment and prevention of these cancers. growth of mutant blood stem and progenitor cells and ii) identify therapeutic vulnerabilities of MDS driven by these mutations that will be used for the development of new treatment against these incurable malignancies.
Specifically we discovered: First that splicing factor (SF) gene mutations drive clonal expansion of mutant cells by corrupting telomere maintenance (McLoughlin et al, Nature Genetics 2025). Second that mitochondrial metabolism is a therapeutic vulnerability of SF3B1-mutamnt MDS and that inhibition of specific genes/proteins inhibited mutant cell growth. Going forward, we will continue to investigate the molecular basis of these observations and work to develop therapeutic approaches for patients with SF-mutant MDS and CH. We anticipate that these findings will lead directly to therapeutic advances that will improve the survival and quality of life of patients with SF-mutant MDS and potentially also help to prevent the development of these cancers.
Specifically we discovered: First that splicing factor (SF) gene mutations drive clonal expansion of mutant cells by corrupting telomere maintenance (McLoughlin et al, Nature Genetics 2025). Second that mitochondrial metabolism is a therapeutic vulnerability of SF3B1-mutamnt MDS and that inhibition of specific genes/proteins inhibited mutant cell growth. Going forward, we will continue to investigate the molecular basis of these observations and work to develop therapeutic approaches for patients with SF-mutant MDS and CH. We anticipate that these findings will lead directly to therapeutic advances that will improve the survival and quality of life of patients with SF-mutant MDS and potentially also help to prevent the development of these cancers.