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.
