Research groups
Andrea Pellagatti
PhD
University Research Lecturer
I have received my undergraduate degree from the University of Milan (Italy), and I have obtained my PhD in Oxford in 2007 on the study of myeloid disorders using microarray technology.
My research has primarily concerned the investigation of the molecular pathogenesis of the myelodysplastic syndromes (MDS), a heterogeneous group of myeloid malignancies. We have performed the largest study to date of gene expression profiling in MDS CD34+ cells and this work has resulted in the identification of key dysregulated genes and pathways in this disorder. We have also identified a gene expression profiling-based signature for assessing prognosis in MDS. More recently we have explored the interconnections among mutations, gene expression, clinical variables and patient survival in MDS, and we showed that the transcriptome was the most powerful predictor of outcome. Our study of the MDS transcriptome using RNA sequencing has identified key downstream target genes that are aberrantly spliced in association with spliceosome gene mutations in MDS. Mutation of the splicing factor SF3B1 is strongly associated with the MDS subtype MDS-RS and we have implicated aberrant splicing of the downstream target gene ABCB7 in the pathophysiology of MDS-RS. In collaborative studies, we have shown that U2AF1 and SF3B1 mutations in myeloid malignancies induce oncogenic isoforms of IRAK4 that are therapeutically targetable (using the IRAK4 inhibitor CA-4948). These data have critical implications for understanding MDS phenotypic heterogeneity and support the development of therapies targeting splicing abnormalities.
Using next-generation sequencing technology, we have illuminated the molecular landscape of MDS and we have evaluated the frequency and chronology of mutation acquisition in serial samples from MDS patients progressing to acute myeloid leukaemia (AML).
We are currently using single-cell analysis to determine the transcriptomic changes occurring in the stem cell population of splicing factor mutant MDS, and CRISPR/Cas9 genome editing to model MDS and to investigate the impact of common mutations on the MDS phenotype.
I have served on several departmental committees and on international scientific panels, including the International Working Group for the Prognosis of MDS.
Key publications
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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
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MDMX acts as a pervasive preleukemic-to-acute myeloid leukemia transition mechanism.
Journal article
Ueda K. et al, (2021), Cancer Cell
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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
Recent publications
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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
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Pathophysiologic and clinical implications of molecular profiles resultant from deletion 5q.
Journal article
Adema V. et al, (2022), EBioMedicine, 80
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PRELIMINARY PROSPECTIVE MOLECULAR ANALYSIS OF PLCBETA1 AND PLCGAMMA2 IN MDS PATIENTS TREATED WITH AZACITIDINE AND VENETOCLAX
Conference paper
De Stefano A. et al, (2022), HAEMATOLOGICA, 107, 65 - 65
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BCL-2 Inhibitor ABT-737 Effectively Targets Leukemia-Initiating Cells with Differential Regulation of Relevant Genes Leading to Extended Survival in a NRAS/BCL-2 Mouse Model of High Risk-Myelodysplastic Syndrome.
Journal article
Gorombei P. et al, (2021), Int J Mol Sci, 22
ORCID
0000-0002-6122-0221