Vyas Group: Normal and Leukaemic Blood Stem/Progenitor Cell Biology
We aim to understand the fundamental biological processes underlying normal and malignant haematopoiesis and translate this to improve patient outcomes through new rational therapies.
Our laboratory is interested in understanding the process of normal blood development and how this is perturbed in blood cancers such as Acute Myeloid Leukaemia (AML) and myeloma.
Despite scientific advances, clinical outcomes for patients with these blood cancers remain poor and the majority of patients relapse after treatment. To improve outcomes, a better understanding of the cellular and molecular mechanisms underlying the disease are needed. Recently there has been significant progress in understanding the genetic basis of myeloid malignancies and myeloma, but the mechanisms of oncogenesis remain unclear. A critical question is how genetic and epigenetic regulation is disrupted in leukaemia stem cells (in AML) and therapy resistant myeloma cells in myeloma, which are thought to drive disease relapse. A strong understanding of normal human haematopoiesis forms a foundation for studying how cell fate decisions are perturbed in these blood cancers.
To study normal and malignant haematopoiesis, we use single cell approaches and combine state-of-the-art transcriptional, epigenetic and functional assays in appropriate models. Examples of our work include:
- Single-cell analysis reveals the continuum of human lympho-myeloid progenitor cells. (Karamitros, Stoilova et al. Nature Immunology, 19:85-97, 2018)
- Studying the impact of clonal heterogeneity on leukaemia and myeloma biology to understand the genetic basis of therapeutic response. (Quek et al., 2016, JEM; Quek et al., 2017, Nature Medicine, Invited revision under review)
- Translational work with partners in industry towards development of new therapies for AML including: IDH2 inhibitor enasidenib (Celgene and Agios) (Amatangelo et al. Blood 130:732-741 (2017) and Stein et al Blood 130(6):722-731 (2017), humanised anti-CD47 monoclonal antibody with Forty Seven, Inc., novel differentiation therapies with OxStem Oncology and IDH2 inhibitor (Celgene).
- Understanding molecular mechanisms of myeloid pre-leukaemia and leukaemia in Down Syndrome (Roberts et al., 2013, Blood).
- Investigating the cellular and molecular basis of clonal dominance in Age-Related Clonal Haematopoiesis (ARCH).
A valuable resource directing our work, and that of others, is the Haematopoietic Cell Biobank, one of the largest banks of haematological samples in the United Kingdom (around 14,000 samples), which is coordinated and managed by our laboratory. A fundamental strength of our group is the ability to integrate this clinical resource with state-of-the-art flow cytometry to purify rare haematopoietic cell populations for functional and molecular analyses. The WIMM provides a world class environment for these analyses with Single Cell, Genomic Engineering and Virus Production Facilities, as well as sequencing facilities here and at the Wellcome Trust Centre for Human Genetics. Group members also have access to computational resources and training at the WIMM and University wide.
The laboratory has a mix of graduate (DPhil) students and postdoctoral scientists from clinical and scientific backgrounds, as well as experienced research assistants. We emphasise a rigorous approach to experimental design and data analysis. In this stimulating environment, we aim to train the next generation of basic and clinical researchers whilst making a valuable contribution to this exciting and clinically important area of research.
- University of Oxford - MRC Molecular Haematology Unit (Catherine Porcher, Claus Nerlov, Irene Roberts, Tom Milne, Sten Jacobsen and Adam Mead), MRC Human Immunology Unit (Vincenzo Cerundolo), Ludwig Cancer Institute Oxford (Skirmantas Kriaucionis).
- UK Clinical Networks: AML working Party – S Freeman, Richard Dillon, Robert Hills, Charles Craddock, N Russell. TAP and IMPACT Trial Consortia – Charles Craddock
- Stanford University – Prof Irving Weissman and Dr Ravi Majeti
- Institut Gustave Roussy – Prof Olivier Bernard, Prof Virginine Penard-Lacronique, Dr Stéphane de Botton
- University of Cambridge – Prof Bertie Göttgens
Clinical Studies and trials
Chief Investigator: Prof Paresh Vyas
Celgene AML 004 and AML005 – International Phase III trials of a first-in-class oral enasidenib, an IDH2 inhibitor in Acute Myeloid Leukaemia. Sponsored by Celgene.
Celgene MDS003 - International Phase III trial of a first-in-class oral DNA and RNA demethylation inhibitor in Acute Myeloid Leukaemia. Sponsored by Celgene.
Celgene AML 005 - Azacitidine +/- IDH2 inhibitor AG221 inpatients with newly diagnosed, previously untreatd AML patients.
Chief Investigator: Dr Lynn Quek
AGILE - Azacitidine +/- IDH1 inhibitor (AG120/ Ivosidenib) in newly diagnosed, previously untreatd AML patients.
We regularly host both work experience students and visiting biomedical/medical science students.
Professor Vyas has given short talks about AML and the importance of single-cell approaches to study a heterogeneous disease.