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We study the molecular mechanisms involved in disease initiation and progression in the myelodysplastic syndromes (MDS) in order to better understand disease pathogenesis and to identify new therapeutic targets and prognostic markers for this disorder.

Boultwood volcano plot
A volcano plot showing the differentially expressed genes in MDS patients harbouring a known splicing factor mutation compared to healthy controls

The MDS are clonal myeloid malignancies showing frequent evolution to acute myeloid leukaemia (AML). The bone marrow cells of MDS patients harbour genetic abnormalities, including cytogenetic aberrations and gene mutations. We believe that gaining a greater understanding of the complex genetic landscape of MDS is pivotal to better characterise the disease and to identify new therapeutic approaches.

5q- syndrome

One of the focuses of our studies is the investigation of MDS patients with loss of the long arm of chromosome 5 [del(5q)], the most common cytogenetic abnormality found in MDS.

Our group identified the commonly deleted region in 5q- syndrome and demonstrated that patients with this MDS subtype show haploinsufficiency (50% reduction in expression) of the ribosomal gene RPS14. We subsequently showed that p53 activation (secondary to haploinsufficiency of RPS14) underlies the anaemia in the 5q- syndrome. Our work has been instrumental in the elucidation of the molecular basis of the 5q- syndrome and in the determination of the disease mechanism that underlies this disorder.

MDS transcriptome

Several years ago, we initiated a major project concerning global gene expression profiling in MDS haematopoietic stem cells. Our study of the MDS transcriptome has yielded valuable insights into the pathophysiology and molecular pathogenesis of MDS, and has identified novel prognostic markers and therapeutic targets for this disorder. More recently we have provided deep insights into how gene mutations drive the changes in the MDS transcriptome. Our transcriptome-based studies of MDS have proven most fruitful, and we have established an international reputation in this field. 

Splicing factor mutations

The identification of frequent mutations in members of the RNA splicing machinery in MDS implicate abnormalities of mRNA splicing in the pathogenesis of this disorder. As part of a collaborative study, we have reported frequent mutation of the splicing factor SF3B1 in MDS patients with a particular enrichment in patients whose disease is characterised by ring sideroblasts (MDS subtypes RARS and RCMD-RS), making this the first gene to be strongly associated with a specific morphological feature in MDS.

We have identified the aberrantly spliced downstream target genes associated with SF3B1 mutations and other common splicing factor mutations in MDS. The impact of these key target genes on MDS disease pathophysiology is an ongoing interest in our group. We have implicated aberrant splicing of the downstream target gene ABCB7 in the pathophysiology of SF3B1-mutant RARS.

MDS disease progression

The molecular events driving MDS progression to AML remain poorly understood. We have determined the frequency and chronology of myeloid gene mutation acquisition during disease progression in MDS using a NGS myeloid gene panel, identifying specific mutations that are associated with disease evolution, and illuminating the role of subclone development in MDS progression.

CRISPR/Cas9 gene editing

CRISPR/Cas9 genome editing has brought about an exciting opportunity to further elucidate the function of mutations in MDS and leukaemia. We have used this technology to correct gene mutations in leukaemia cells. We are currently using CRISPR/Cas9 to model MDS and to investigate the impact of common mutations on the MDS phenotype.

Our team

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