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The main focus of our group is the investigation of the molecular mechanisms involved in disease initiation and progression in the myeloid malignancy myelodysplastic syndromes (MDS). We use a variety of techniques, including next-generation sequencing (RNA-seq), induced pluripotent stem cell (iPSC) technology and CRISPR/Cas9 gene editing, in order to better understand disease pathogenesis and to identify new therapeutic targets and prognostic markers for MDS.

Boultwood

About the research

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. We have provided deep insights into how recurrent gene mutations drive the changes in the MDS transcriptome. Most recently, using RNA-seq we have identified key aberrantly spliced genes and dysregulated pathways in bone marrow CD34+ cells and myeloid precursors of MDS patients with commonly occurring splicing factor mutations. We have performed functional studies involving shRNA-mediated gene knockdown to determine the impact of some of the identified splicing abnormalities on the cellular function in the main haematopoietic cell lineages affected in MDS.

CRISPR/Cas9 is powerful and versatile tool for genome editing, and we have used this technology to to introduce or correct specific gene mutations in leukaemia cells. We are currently using CRISPR/Cas9 gene editing to investigate the impact of recurrent mutations on the MDS phenotype. In addition, we are using iPSC technology and CRISPR/Cas9 to model the myeloid malignancy chronic myelomonocytic leukaemia and for drug discovery.

We also plan to perform single-cell mutation profiling and RNA sequencing to identify new therapeutic targets/treatments from the transcriptomic analysis of single haematopoietic stem cells (HSCs) from MDS patients with splicing factor gene mutations. The analysis of the generated single-cell data will allow for the identification of druggable targets, and drugs known to target them, within different mutation-defined HSC subpopulations in individual MDS patients.

The use of CRISPR/Cas9 and iPSCs for disease modelling and for drug discovery, and single-cell analysis of MDS HSCs are possible areas in which student projects will be undertaken.

Training Opportunities

Students will be trained in a variety of techniques routinely used in the lab, including next-generation sequencing (RNA-seq), cell culture and lentiviral transduction, iPSC technology and CRISPR/Cas9 gene editing.

Students are encouraged to attend the MRC Weatherall Institute of Molecular Medicine DPhil Course, which takes place in the autumn of their first year. Running over several days, this course helps students to develop basic research and presentation skills, as well as introducing them to a wide-range of scientific techniques and principles, ensuring that students have the opportunity to build a broad-based understanding of differing research methodologies.

Generic skills training is offered through the Medical Sciences Division's Skills Training Programme. This programme offers a comprehensive range of courses covering many important areas of researcher development: knowledge and intellectual abilities, personal effectiveness, research governance and organisation, and engagement, influence and impact. Students are actively encouraged to take advantage of the training opportunities available to them.

As well as the specific training detailed above, students will have access to a wide-range of seminars and training opportunities through the many research institutes and centres based in Oxford.

The Department has a successful mentoring scheme, open to graduate students, which provides an additional possible channel for personal and professional development outside the regular supervisory framework. We hold an Athena SWAN Silver Award in recognition of our efforts to build a happy and rewarding environment where all staff and students are supported to achieve their full potential.

Publications

 

Pellagatti A, Armstrong RN, Steeples V, Sharma E, Repapi E, Singh S, Sanchi A, Radujkovic A, Horn P, Dolatshad H, Roy S, Broxholme J, Lockstone H, Taylor S, Giagounidis A, Vyas P, Schuh A, Hamblin A, Papaemmanuil E, Killick S, Malcovati L, Hennrich ML, Gavin AC, Ho AD, Luft T, Hellstrom-Lindberg E, Cazzola M, Smith CWJ, Smith S, Boultwood J. Impact of spliceosome mutations on RNA splicing in myelodysplasia: dysregulated genes/pathways and clinical associations. Blood. 2018; 132(12):1225-40.  
Yip BH, Steeples V, Repapi E, Armstrong RN, Llorian M, Roy S, Shaw J, Dolatshad H, Taylor S, Verma A, Bartenstein M, Vyas P, Cross NC, Malcovati L, Cazzola M, Hellstrom-Lindberg E, Ogawa S, Smith CW,    Pellagatti A, Boultwood J. The U2AF1S34F mutation induces lineage-specific splicing alterations in myelodysplastic syndromes. J Clin Invest. 2017; 127(6):2206-21.  
Dolatshad H, Pellagatti A, Liberante FG, Llorian M, Repapi E, Steeples V, Roy S, Scifo L, Armstrong RN, Shaw J, Yip BH, Killick S, Kusec R, Taylor S, Mills KI, Savage KI, Smith CW, Boultwood J. Cryptic splicing events in the iron transporter ABCB7 and other key target genes in SF3B1-mutant myelodysplastic syndromes. Leukemia.    2016; 30(12):2322-31.  

Valletta S, Dolatshad H, Bartenstein M, Yip BH, Bello E, Gordon S, Yu Y, Shaw J, Roy S, Scifo L, Schuh A, Pellagatti A, Fulga TA, Verma A, Boultwood J. ASXL1 mutation correction by CRISPR/Cas9 restores gene function in leukemia cells and increases survival in mouse xenografts. Oncotarget. 2015; 6(42):44061-71.

Gerstung M, Pellagatti A, Malcovati L, Giagounidis A, Porta MG, Jadersten M, Dolatshad H, Verma A, Cross NC, Vyas P, Killick S,  Hellstrom-Lindberg E, Cazzola M, Papaemmanuil E, Campbell PJ, Boultwood J. Combining gene mutation with gene expression data improves outcome prediction in myelodysplastic syndromes. Nat Commun. 2015; 6:5901.   
Pellagatti A, Benner A, Mills KI, Cazzola M, Giagounidis A, Perry J, Malcovati L, Della Porta MG, Jädersten M, Verma A, McDonald EJ, Killick S, Hellström-Lindberg E, Bullinger L, Wainscoat JS, Boultwood J. Identification of gene expression-based prognostic markers in the hematopoietic stem cells of patients with myelodysplastic syndromes. J Clin Oncol. 2013; 31(28):3557-64.  

Supervisor