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Jacqueline Boultwood

BSc (Hons), PhD

Professor of Molecular Haematology

  • Director of Graduate Studies in the Medical Sciences Division

Molecular pathogenesis of myeloid malignancies

My research studies concern the investigation of the molecular pathogenesis of myeloid malignancies, including the myelodysplastic syndromes (MDS) and acute myeloid leukaemia (AML). 

My work has focused on MDS, a heterogeneous group of clonal myeloid disorders. These studies have been instrumental in the determination of the molecular pathogenesis of several subtypes of MDS including the 5q- syndrome and MDS with ring sideroblasts (MDS-RS). Our research identified the commonly deleted region of the del(5q) in the 5q- syndrome and showed that p53 activation underlies the anaemia in this disorder. 

Using next generation sequencing technology we have illuminated the molecular landscape of MDS and the genetic basis of disease progression to AML. Our study of the MDS transcriptome has yielded valuable insights into the molecular pathophysiology of MDS, and has identified new prognostic markers and therapeutic targets for this disorder. Our work provides deep insights into how gene mutations drive the changes in the MDS transcriptome. 

Splicing factor genes are the most commonly mutated genes in MDS, and we have identified novel aberrantly spliced genes and dysregulated pathways in splicing factor mutant MDS. Mutation of the splicing factor SF3B1 is strongly associated with MDS-RS and we demonstrated mis-splicing of the iron transporter ABCB7, a major driver of ring sideroblast formation, in this MDS subtype. In collaborative studies we have shown that U2AF1 and SF3B1 mutations induce oncogenic isoforms of IRAK4 in myeloid malignancies that are therapeutically targetable (CA-4948, emavusertib). It is now recognised that the commonly mutated splicing factors have convergent effects on aberrant splicing of mRNAs that promote NF-κB signaling and on R-loop elevation leading to DNA damage. We are currently using single-cell analysis to determine the transcriptomic changes occurring in the stem cell population of splicing factor mutant MDS. Our data have critical implications for understanding MDS phenotypic heterogeneity and support the development of therapies targeting splicing abnormalities. 

We are also using CRISPR/Cas9 genome editing together with induced pluripotent stem cell (iPSC) technology to model chronic myelomonocytic leukaemia and for drug discovery.

I have served on several advisory committees and scientific panels, including for NHLBI, Leukaemia UK and the International Working Group for the Prognosis of MDS. I have served as a member of the Editorial Boards of many medical and scientific journals, including Blood, the British Journal of Haematology, and Haematologica, and as an Associate Editor of Molecular Biotechnology.

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