2023: Asger Jakobsen

Asger Jakobsen studied medicine at the University of Cambridge, before moving to Oxford for clinical school where he graduated in 2014. During clinical school and in his subsequent work as a foundation doctor he developed a strong interest in haematology, and particularly the development of blood cancers.

He joined the MRC Weatherall Institute of Molecular Medicine (WIMM) in 2016 as an NIHR Clinical Research Career Development Fellow in Paresh Vyas' group, where he began working on a project to understand how mutations lead to pre-leukaemic clonal expansion in older age. In 2017, he was awarded an MRC Clinical Research Training Fellowship, joint-funded by Leuka (now Leukaemia UK), enabling him to continue this work as a DPhil student.

For his DPhil, he decided to focus on the question of how pre-leukaemic mutations that arise in blood stem cells lead to a growth advantage, resulting in clonal expansion over time. In 2014, it was discovered that such mutations are commonly found in healthy older people and predispose to the development of blood cancers, as well as other adverse outcomes including cardiovascular disease and severe infection. Most mutations occur in just two genes, called DNMT3A and TET2, which regulate DNA methylation, an epigenetic mark involved in switching genes on and off. This condition, known as age-related clonal haematopoiesis, may be present for many years before the development of cancer and therefore makes it possible to identify individuals who are at risk and potentially intervene early before the onset of disease.

Previous work had shown that DNMT3A and TET2 mutations confer a selective advantage but was unclear how they affect the human blood system and why they lead to clonal expansion. To provide a foundation for understanding this, Asger decided to study clonal haematopoiesis in humans. This required bone marrow samples from healthy people, so he established a study, called the MARCH Study, in collaboration with teams at the Nuffield Department of Orthopaedics, Rheumatology and Musculoskeletal Science (NDORMS) and the Nuffield Orthopaedic Centre to collect bone marrow and blood samples from over 200 individuals undergoing hip replacement surgery. This enabled him to identify individuals with clonal haematopoiesis and study the consequences of mutations on blood production.

Using a method for analysing how mutations change gene expression at the single-cell level (TARGET-seq+), Asger and his colleagues were able to show that clones with DNMT3A and TET2 mutations have distinct patterns of clonal expansion. Nonetheless, most clonal expansion occurs at the level of haematopoietic stem cells (HSC). They found that expression of inflammatory and ageing genes was increased in individuals with clonal haematopoiesis compared normal individuals. However, stem cells with the mutation appear to be less affected differently by inflammation than cells without the mutation. This supports a model whereby clones are gradually selected because they are more resistant to the deleterious impact of inflammation and ageing. This work is currently in revision.

During his DPhil, Asger also worked with Sven Turkalj to develop a novel method, called 'GTAC', for combining genotyping with chromatin accessibility analysis in single cells. This method was published in Cell Stem Cell. For the first time, this makes it possible to examine how somatic mutations alter the epigenetic landscape in primary human samples. Given that many mutations, both in clonal haematopoiesis and in cancer, perturb gene regulation, this method is likely to be transformative in identifying the mechanisms by which mutations alter cell function and promote cancer development. By revealing clone-specific molecular signatures, GTAC can be used to understand how genetic and epigenetic evolution allow malignant subclones to evade treatment and cause disease relapse.

In 2022, Asger was awarded an ASH-BSH Abstract Achievement Award for his abstract on the clonal haematopoiesis work, which he presented at the ASH Annual Meeting in 2022.

Since finishing his DPhil, Asger has continued in the Vyas lab, building on his work in clonal haematopoiesis to identify mechanisms by which these abnormal cells are selected. He says: 'None of this work would have been possible without all the support received from my supervisor, Paresh Vyas, members of the Vyas lab, our collaborators in the Dick and Xie labs (both at Princess Margaret Cancer Centre, Toronto), the Botnar Research Centre and Nuffield Orthopaedic Centre and the patients who took part in the study. It has been a joy to work at the WIMM and has inspired me to pursue a career in haematology research.'