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Wellcome - MRC Cambridge Stem Cell Institute

 

107-Green-2017Professor Tony Green

Haematopoiesis and myeloid malignancies

Email: arg1000@cam.ac.uk

Laboratory: Cambridge Stem Cell Institute, Jeffrey Cheah Biomedical Centre

Departmental Affiliation: Haematology

 

Biography

Tony Green studied medicine (University of Cambridge and University College Hospital, London), subsequently trained in haematology (Royal Free Hospital and Cardiff) and gained his PhD studying oncogenic retroviruses (ICRF, London 1987). Following a post-doctoral period studying haematopoiesis at the Walter and Eliza Hall Institute (Melbourne), he moved to Cambridge in 1991 as a Wellcome Trust Clinical Senior Fellow and Honorary Consultant Haematologist.  He was appointed Professor of Haemato-oncology in the University of Cambridge in 1999, Head of the University Department of Haematology in 2000, and Director of the Wellcome-MRC Cambridge Stem Cell Institute in 2016.

 His early research explored the transcriptional control of normal blood stem cells and more recently the mechanisms by which stem cells are subverted to cause haematological malignancies, using the myeloproliferative neoplasms as a tractable model.  In work which spans basic, translational and clinical research he identified key causal mutations, described their biological consequences, led practice-changing clinical studies and discovered basic mechanisms of broad relevance for both cancer biology and cytokine signalling.

He has held multiple academic, clinical and educational leadership roles, both nationally and internationally, has been appointed to visiting professorships at several universities, was elected Fellow of the Academy of Medical Sciences (2001) and President of the European Haematology Association (2015-2017). Recent awards include the Jean Bernard Award by the European Haematology Association (2020) and the Donald Metcalf award by the International Society for Experimental Hematology (2021).  

 

Funding

Wellcome, Cancer Research UK, WBH Foundation

 

External links

www.cimr.cam.ac.uk/research/affiliated/green

 

 

The stem/progenitor landscape is reshaped by mutant CALR in essential thrombocythaemia
Single-cell RNA sequencing of mouse haematopoietic stem and progenitor cells (HSPCs) shows an increase in HSCs and megakaryocyte (MK) progenitor cells in CALR mutant mice, as shown by the arrow in the figure to the left. Force-directed graphical representation of the same data (right) identifies a new intermediate population (arrow) within a trajectory linking HSCs to MK progenitors. 

 

 

Research

The Green Lab focuses on the mechanisms whereby blood stem cells are subverted during the genesis of haematological malignancies.  Over the past decade we have increasingly concentrated on JAK/STAT signalling which is dysregulated in many cancers and plays a key role in multiple stem cell systems.  In particular we have explored the molecular and cellular pathogenesis of a group of pre-leukaemic disorders, the myeloproliferative neoplasms (MPNs), in studies which have spanned basic, translational and clinical research. The myeloproliferative neoplasms harbour mutations that activate the JAK/STAT pathway, are experimentally tractable and provide a paradigm for the earliest stages of tumorigenesis, inaccessible in other cancers.  We described the MPN "mutational landscape" and identified causal mutations which revolutionised their diagnosis and catalysed development of therapeutically valuable JAK-family tyrosine kinase inhibitors. Our more basic research is illuminating the mechanisms whereby the JAK/STAT pathway regulates diverse aspects of cellular function including chromatin biology, DNA replication, genome-wide transcriptional programs and stem cell fate.  Recent highlights include: the first demonstration in any cancer that mutation order affects stem and progenitor behaviour, thus influencing clinical presentation, disease outcome and response to therapy; the description of paradigm-shifting non-canonical mechanisms of JAK/STAT signalling; a new biological classification and personalised predictions based on a knowledge bank; and the use of somatic mutations to reveal human cellular ancestry and stem cell dynamics. 

 

Green group 2020

 

Group Members

Hugo Bastos, Jeremy Deuel, Tina Hamilton, Juan Li, Stephen Loughran, Dean Pask, Daniel Prins, Rachel Sneade, Michelle Wantoch, Matthew Williams.

 

Plain English

Blood stem cells produce a large number of cell types and are the best studied adult stem cell system. We are interested in the molecular mechanisms that control the formation and behavior of normal blood stem cells and how these processes are perturbed during the development of haematological malignancies. In particular we have focussed on a group of human pre-leukaemic disorders, called the myeloproliferative neoplasms, in studies which span basic, translational and clinical research. Our basic studies are illuminating the fundamental mechanisms by which these disorders arise, and have a broad relevance for other cancers and for the normal process of blood cell formation. Moreover, our results have already had major clinical impact, with new diagnostic approaches embedded in international guidelines and multiple JAK inhibitors in clinical trials. 

 

Key Publications