LAUSR

Our research focuses on the mechanisms whereby blood stem cells are subverted during the genesis of haematological malignancies.  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. These disorders are experimentally tractable and provide a model for the earliest stages of tumorigenesis, inaccessible in other cancers. In work which transformed MPN diagnosis and catalysed development of therapeutic JAK inhibitors, we and others identified phenotypic driver mutations in JAK2 and CALR which activate the JAK/STAT pathway and are present in most MPN patients. We are employing a variety of genomic approaches to explore MPN biology and improve patient management. In parallel we are investigating the functional consequences of JAK2 and CALR mutations in work which has led to unexpected insights into cancer biology as well as normal cytokine signalling. Recent highlights include: (i) 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); (ii) description of unexpected non-canonical mechanisms of JAK/STAT signalling (Dawson et al Nature 2009; Dawson et al Cell Reports 2013); 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); (iv) the use of somatic mutations as clonal markers 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 latter approach is broadly applicable and allows interrogation of human stem cell dynamics in young and old, in health and disease.