Research groups
Colleges
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.
Key publications
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U2AF1 mutations induce oncogenic IRAK4 isoforms and activate innate immune pathways in myeloid malignancies.
Journal article
Smith MA. et al, (2019), Nat Cell Biol, 21, 640 - 650
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Impact of spliceosome mutations on RNA splicing in myelodysplasia: dysregulated genes/pathways and clinical associations.
Journal article
Pellagatti A. et al, (2018), Blood, 132, 1225 - 1240
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The U2AF1S34F mutation induces lineage-specific splicing alterations in myelodysplastic syndromes.
Journal article
Yip BH. et al, (2017), J Clin Invest, 127, 2206 - 2221
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Cryptic splicing events in the iron transporter ABCB7 and other key target genes in SF3B1-mutant myelodysplastic syndromes.
Journal article
Dolatshad H. et al, (2016), Leukemia, 30, 2322 - 2331
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Combining gene mutation with gene expression data improves outcome prediction in myelodysplastic syndromes.
Journal article
Gerstung M. et al, (2015), Nat Commun, 6
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Identification of gene expression-based prognostic markers in the hematopoietic stem cells of patients with myelodysplastic syndromes.
Journal article
Pellagatti A. et al, (2013), J Clin Oncol, 31, 3557 - 3564
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A p53-dependent mechanism underlies macrocytic anemia in a mouse model of human 5q- syndrome.
Journal article
Barlow JL. et al, (2010), Nat Med, 16, 59 - 66
Recent publications
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Current landscape of translational and clinical research in myelodysplastic syndromes/neoplasms (MDS): Proceedings from the 1st International Workshop on MDS (iwMDS) Of the International Consortium for MDS (icMDS).
Journal article
Bewersdorf JP. et al, (2023), Blood Rev, 60
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A miRNA screening identifies miR-192-5p as associated with response to azacitidine and lenalidomide therapy in myelodysplastic syndromes.
Journal article
Mongiorgi S. et al, (2023), Clin Epigenetics, 15
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Finding consistency in classifications of myeloid neoplasms: a perspective on behalf of the International Workshop for Myelodysplastic Syndromes.
Journal article
Zeidan AM. et al, (2022), Leukemia
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An agenda to advance research in MDS: A TOP 10 Priority List from the first international workshop in MDS (iwMDS).
Journal article
Stahl M. et al, (2022), Blood Adv
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Splicing factor mutations in the myelodysplastic syndromes: Role of key aberrantly spliced genes in disease pathophysiology and treatment.
Journal article
Pellagatti A. and Boultwood J., (2022), Adv Biol Regul
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Activation of targetable inflammatory immune signaling is seen in myelodysplastic syndromes with SF3B1 mutations.
Journal article
Choudhary GS. et al, (2022), Elife, 11
ORCID
0000-0002-4330-2928