A R Green
Wellcome – MRC Cambridge Stem Cell Institute and Department of Haematology, University of Cambridge
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: (i) the first demonstration in any cancer that mutation order affects stem and progenitor behaviour, thus influencing clinical presentation, disease outcome and response to therapy (Ortmann et al NEJM 2015); the description of paradigm-shifting non-canonical mechanisms of JAK/STAT signalling (Dawson et al Nature 2009; Park et al EMBO J 2016); (iii) a new MPN classification based on causal biological mechanisms and the development of personalised predictions tailored to individual patients (Grinfeld et al NEJM 2018).
Most recently we harnessed spontaneous somatic mutations as clonal markers, and (with Kent and Campbell) used whole genome sequencing to reconstruct the cellular ancestry of human haematopoiesis as a single phylogenetic tree with the fertilized egg at its root (Lee-Six et al Nature 2018). This approach is broadly applicable and allows for the first-time interrogation of stem cell dynamics within human organs, in young and old, in health and disease.
Tony Green studied medicine (University of Cambridge and University College Hospital, London) and trained in haematology (Royal Free Hospital and Cardiff). He gained his PhD studying oncogenic retroviruses (London) and spent a post-doctoral period studying haematopoiesis at the Walter and Eliza Hall Institute (Melbourne), moving to Cambridge in 1991 as a Wellcome Trust Clinical Senior Fellow and Honorary Consultant Haematologist. He was subsequently appointed Professor of Haemato-oncology (1999), Head of the University Department of Haematology (2000), and Director of the Wellcome – MRC Cambridge Stem Cell Institute (2016).
His research has explored the control of normal blood stem/progenitor cells and the mechanisms by which such 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 and led practice-changing clinical studies. His discoveries have also led to fundamental insights 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 multiple universities, elected Fellow of the Academy of Medical Sciences (2001), Newton Abraham Visiting Professor, University of Oxford (2011), Distinguished Visiting Professor Cancer Science Institute, Singapore (2009-10), Grinberg/Wisch Visiting Professor, Mount Sinai Medical Center, New York (2013), and Clement A Finch Visiting Professor, University of Washington (2015) and President of the European Haematology Association (2015-2017).