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Jacqueline Boultwood

BSc (Hons), PhD

Professor of Molecular Haematology

  • Director of Graduate Studies in NDCLS, RDM 2019-2023

Molecular pathogenesis of myeloid malignancies

My research concerns the investigation of the molecular pathogenesis of myeloid malignancies, with a focus on the myelodysplastic syndromes (MDS) and secondary acute myeloid leukaemia. 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 found in this disorder. 

We have generated the largest global gene expression datasets of MDS patient CD34+ cells available and these are widely used as a resource by the international community. 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 (e.g., deregulated SMAD signalling in luspatercept efficacy). 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 recent collaborative studies we have shown that U2AF1 and SF3B1 mutations induce oncogenic isoforms of IRAK4 in myeloid malignancies that are therapeutically targetable with IRAK1/4 inhibitors (e.g. CA-4948, emavusertib). We and others have shown that the commonly mutated splicing factors have convergent effects on aberrant splicing of mRNAs that promote NF-κB signalling and also on R-loop elevation leading to DNA damage.  Our data have critical implications for understanding MDS phenotypic heterogeneity and support the development of therapies targeting splicing abnormalities. 

We are currently 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 the National Heart, Lung, and Blood Institute (NHLBI), Leukaemia UK and the International Working Group for the Prognosis of MDS. I am a member of the Pan-Cancer Analysis of Whole Genomes (PCAWG) Consortium. 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. I have published widely and my h-index is >60. 

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