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Vyas Group: Normal and Malignant Haematopoiesis Lab

Nuffield Division of Clinical Laboratory Sciences MRC Molecular Haematology Unit MRC Weatherall Institute of Molecular Medicine

We aim to understand the fundamental biological processes underlying normal and malignant haematopoiesis and translate this to improve patient outcomes through new rational therapies.

Vyas lead image 2

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 AML 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, but the mechanisms of leukaemogenesis remain unclear. A critical question is how genetic and epigenetic regulation is disrupted in leukaemia stem cells, 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 leukaemia.

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:

  1. Functional and transcriptional characterisation of human progenitor populations to understand lympho-myeloid cell fate decisions. (Karamitros, Stoilova et al. Nature Immunology, Under revision)
  2. 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, Submitted)
  3. Translational work with partners in industry towards development of new therapies for AML including: humanised anti-CD47 monoclonal antibody with Forty Seven, Inc., novel differentiation therapies with OxStem Oncology and IDH2 inhibitor (Celgene).
  4. Understanding molecular mechanisms of myeloid pre-leukaemia and leukaemia in Down Syndrome (Roberts et al., 2013, Blood).
  5. 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. 

Our team

Collaborations

  1. 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). 
  2. UK Clinical Networks: AML working Party – S Freeman, Richard Dillon, Robert Hills, Charles Craddock, N Russell. TAP and IMPACT Trial Consortia – Charles Craddock
  3. Stanford University – Prof Irving Weissman and Dr Ravi Majeti
  4. Institut Gustave Roussy – Prof Olivier Bernard, Prof Virginine Penard-Lacronique, Dr Stéphane de Botton
  5. University of Cambridge – Prof Bertie Göttgens

Clincal Studies and trials

Chief Investigator: Prof Paresh Vyas

Camellia – First-in-class Phase I trial of Humanized Monoclonal Antibody anti-CD47 in Acute Myeloid Leukemia.  This is an academically funded, 7-year collaboration between my laboratory and Weissman Laboratory Stanford University. Sponsored by Stanford University. Oxford University is Sponsor in the EU. Oxford Oncology Clinical Trials Unit is running this multi-centre UK trial.

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.

Lab Alumni

Alex Sternberg

Nicolas Goardon

Boris Guyot

Gaetan Juban

Ludovic Lhermitte

Georg Otto

Kelly Perkins

Kelly Soady

Veronica Valverde-Garduno

Terri Cornforth

Helen Doolittle

Julia Draper

Isla Hamlett

Sinead Hayes

Christianne Kuhl

Alice Norton

Neil Rodrigues

Marina Samitch

Anna Schuh

Joanna Bonnici

Members of the lab have been involved in public engagement activities at the MRC Festival of  Medical Research and the Royal Society Summer Science Exhibition. 

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.

Other Videos

Acute Myeloid Leukaemia (Prof Vyas) 

Revealing Hidden Mutations - Cancer (Prof Vyas) 

 


Related research themes

We seek to understand the causes of diseases of the blood and other malignancies, from a molecular to systems level, with a focus on blood cancers, rare inherited conditions and the tumour microenvironment. We use and develop innovative techniques to drive research in this area, and are committed to bringing about change in clinical diagnosis and practice. Our pathologists discovered many of the biomarkers now used routinely in clinical practice, translate laboratory findings into clinical tests and are developing digital pathology initiatives.
Haematology and Pathology
Our research is focused on both blood cancers (myeloid and lymphoid malignancies) and solid tumours, such as breast, colorectal, endocrine and lung cancers, with a number of drug discovery efforts and clinical trials taking place within the department. By understanding the basic biology and underlying disease mechanisms we aim to find effective new biomarkers and treatment approaches.
Cancer Biology
Understanding the fundamental biology that drives embryonic development and tissue maintenance provides the basis of much of our research into blood diseases, the cardiovascular system and rare genetic conditions.
Stem Cells and Developmental Biology
We are committed to translating our innovative research into clinical benefit. From new methods of diagnosing chronic conditions, to finding the latest treatments for diabetes, cancer, heart disease, stroke and rare diseases, our department is involved in hundreds of clinical studies every year.
Clinical Studies and Trials
Employing a range of genetic techniques, we probe the fundamental causes of disease. Our expertise spans identification of causative genes in rare inherited diseases, through to elucidating complex gene regulatory pathways and exploration of susceptibility to common disease through genome-wide association studies. We use cutting edge techniques to manipulate the genome to determine how particular genes work and study how variants in regulatory DNA may contribute to common disease. An important overall aim is to improve the management of human genetic diseases.
Genetics, Genomics and Genome Biology
Building on critical findings from our research streams, we are initiating new drug discovery programmes. Many of our researchers are engaged in target discovery and target validation research – elucidating molecular pathways that can be manipulated for disease modification.
Experimental Therapeutics
A raft of cellular and molecular biology techniques underpin much of the work we do to elucidate the mechanisms of disease. We use established techniques to answer new questions and also develop our own novel and unique methodologies to drive further innovation.
Cellular and Molecular Biology