Nerlov Group - Single Cell Biology and Genetics of Hematopoietic Stem- and Progenitor cells in Blood Cancer and Ageing

About the Research

The Nerlov laboratory studies the fundamental processes by which blood stem cells sustain blood cell production throughout life, and how ageing and haematological malignancies perturb this process. 

We use single cell genomic technologies (ATAC-seq and RNA-seq) to study hematopoietic stem– and progenitor cells in normal development and during ageing, and explore the knowledge generated to unravel the cellular and molecular pathways through which hematopoietic stem- and progenitor cells are specified. We use this knowledge to generate therapeutic strategies for conditions where cell types are under- or overproduced (anaemia, hypereosinophilia, mastocytosis), and to identify the cells and molecular mechanisms involved in the aetiology of acute myeloid leukaemia (AML) and myeloproliferative disorders (MPD). We combine studies of genetically modified mice (lineage tracing, conditional and knock-in mutagenesis, fluorescent reporters, genetic disease models) with molecular and functional analysis of human haematopoiesis, including samples from patients with blood cancer, with the aim of developing pharmacological strategies to treat malignancies and counteract the adverse effects of ageing on the hematopoietic system and overall human physiology.

Genetic and computational modelling of clonal hematopoiesis – from the clinic to the lab and back. Clonal hematopoiesis involves the expansion of mutant hematopoietic stem cell (HSC) clones over time, and becomes frequent in humans with age, reaching a prevalence of ~40% at 75 years. While it is well-established that the presence of expanded mutant HSC populations is associated with a 10-fold elevated risk of development of acute myeloid leukemia (AML) we still do not understand why only some mutant HSC clones expand, or why only a subset of these convert to overt malignancy. In particular, the role of ageing and inflammation in the expansion of mutant HSCs remains to be understood. In this project we will combine genetic modelling of clonal hematopoiesis with in vivo barcoding techniques to measure the frequency with which mutant HSC clones expand, and subsequently transform to AML. Single cell transcriptome and epigenome profiling will be used to identify molecular traits associated with disease development. In parallel, clinical samples from patients with clonal hematopoiesis will be analysed using mathematical modelling and single cell profiling to identify potential drivers of malignant progression.  Potential drivers of clonal expansion and transformation will be functionally validated in the mouse models, the overall aim being to identify therapeutically tractable targets.

The role of ageing in leukaemia development and immune decline. Ageing is associated with decreased production of lymphocytes and erythrocytes, leading to anaemia and declining adaptive immunity. We previously showed that a key feature of hematopoietic ageing is increased platelet-lineage bias of HSCs, which directly suppresses lymphopoiesis (Grover et al., Nat Comms. 2016). Through comprehensive molecular profiling of both hematopoietic and stromal cell types from young and aged mice we have shown that increased TGFb1 and IL-6 signalling in the aged bone marrow regulates this process (Valletta et al., Nat Comms. 2020). We are now investigating how interfering with these signals can counteract ageing of HSCs and associated alterations in the production of blood cells, as well as decrease susceptibility to myeloid malignancies. We are also using genetically accurate models of AML to identify the age-associated changes that contribute to increased prevalence and poor prognosis of AML in elderly patients, with a particular focus on secreted factors that support leukemia progression as putative therapeutic targets.

Additional supervision will be given by Professor Paresh Vyas and Professor Thomas Höfer.

Please see the Weatherall Institute for Molecular Medicine (WIMM) for information about applications for a DPhil in Medical Sciences with groups based in the WIMM.

Training Opportunities

Training is available in the areas of HSC and progenitor biology, biology and treatment of myeloid malignancies, biology of ageing, transcription factor biology, cytokine biology, single cell analysis of HSC/progenitor function, single cell functional genomics (RNAseq, ATACseq), advanced flow cytometry, advanced mouse genetics, CRISPR/Cas9-based genome editing and library screening technologies, advanced bioinformatics, mathematical modelling and machine learning.

Students will be enrolled on the MRC WIMM DPhil Course, which takes place in the autumn of their first year. Running over several days, this course helps students to develop basic research and presentation skills, as well as introducing them to a wide-range of scientific techniques and principles, ensuring that students have the opportunity to build a broad-based understanding of differing research methodologies.

Generic skills training is offered through the Medical Sciences Division's Skills Training Programme. This programme offers a comprehensive range of courses covering many important areas of researcher development: knowledge and intellectual abilities, personal effectiveness, research governance and organisation, and engagement, influence and impact. Students are actively encouraged to take advantage of the training opportunities available to them.

As well as the specific training detailed above, students will have access to a wide-range of seminars and training opportunities through the many research institutes and centres based in Oxford.

All MRC WIMM graduate students are encouraged to participate in the successful mentoring scheme of the Radcliffe Department of Medicine, which is the host department of the MRC WIMM. This mentoring scheme provides an additional possible channel for personal and professional development outside the regular supervisory framework. The RDM also holds an Athena SWAN Silver Award in recognition of our efforts to build a happy and rewarding environment where all staff and students are supported to achieve their full potential.

PUBLICATIONS