Approved research

Understanding clonal haematopoiesis and the preclinical evolution of haematological cancers

Lay summary

Myeloid malignancies encompass a range of related blood cancers, including the myeloproliferative neoplasms (MPN), myelodysplastic syndromes (MDS) and acute myeloid leukaemia (AML). Collectively, they affect 8-10 per 100,000 individuals per year, including both children and adults. Despite significant scientific progress in understanding their pathogenesis, therapeutic advances are lacking and the myeloid malignancies remain lethal to the majority of sufferers. Also, the minority who are cured only do so after treatment with toxic therapies such as intensive chemotherapy or bone marrow transplantation. Advances in cancer genomics have identified the types of acquired gene mutations that drive these cancers, revealing that they are extensively shared between the different subtypes. Also, we and others identified the phenomenon of clonal haematopoiesis (CH), which represents a common pre-clinical phase shared by all myeloid malignancies. More recently, we reported that up to 40% of individuals that develop AML many years before they do so. This provides, for the first time, proof-of-principle that we can identify such individuals in time to intervene and proposes that prevention may be a feasible alternative to treatment in the future. However, at present we have a poor understanding of the factors that promote progression of CH towards a myeloid cancer and have not been able to study MDS and MPN n the same way as we have done for AML. In this study, we will investigate several thousand UK Biobank participants, including some who have developed myeloid malignancy, to describe the pre-clinical history of MPN and MDS and also to identify genetic variants, clinical features, treatments or other factors that promote progression of CH to myeloid malignancy. We anticipate that our findings will improve our ability to identify individuals at risk of developing myeloid cancers and give us insights about the types of factors involved in order to design future strategies to avert or delay the development of these disorders.