The focus of the Nerlov laboratory is combining single cell biology (single cell RNAseq, ATACseq and functional analysis) with advanced mouse genetics to study hematopoietic stem– and progenitor cells in normal development and during ageing. We use the knowledge generated to unravel the cellular and molecular mechanisms through which hematopoietic stem- and progenitor cells are specified, 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 (fluorescent reporters, 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 disease and counteract the adverse effects of ageing on the hematopoietic system and overall human physiology.
Single cell biology of normal hematopoietic stem and progenitor cells:
Hematopoietic stem cells sustain life-long production of lymphocytes, granulocytes, monocytes, erythrocytes and platelets. This occurs through a complex series of progenitor cells that become increasingly lineage-restricted as their differentiation progresses. By combining single cell RNAseq with fluorescent reporter mice and functional single cell assays (HSC transplantation, progenitor differentiation assays) we have identified 5 distinct HSC subtypes (Sanjuan-Pla, Nature 2013; Carrelha, Nature 2018), and novel myelo-erythroid progenitor populations, generating a revised hierarchical model of hematopoiesis (Drissen, Nat. Immunol. 2016; Drissen, Sci. Immunol. 2019).
We will now use advanced genetics (HSC subtype-specific reporters, intersectional lineage tracing) to determine the physiological importance of HSC subtypes and progenitor subsets during steady state, stress hematopoiesis, and leukemogenesis. Parallel studies on human HSCs (collaboration with Vyas laboratory) use barcoding, HSC xenografting and single cell HSC profiling to identify human HSC subtypes and their associated transcriptional programs. We will perform integrated single cell RNAseq and ATACseq analysis, combined with CRISPR-based library screens, to determine how transcriptional and epigenetic regulators interact to generate HSC and progenitor fate restriction. In addition, we will investigate how leukemogeneic mutations collaborate through their effects on gene expression and chromatin accessibility (di Genua, Cancer Cell 2020) to determine the leukaemia phenotype using genetic modelling and single cell molecular profiling of human patient samples from myeloid malignancies, including acute erythroid leukaemia and systemic mastocytosis.
The role of ageing in leukaemia development and immune decline:
We previously showed that ageing leads to hematopoietic platelet-lineage bias due to expansion of platelet-biased HSCs (Grover, Nat. Comms. 2016), a process that contributes to immune-senescence. Through comprehensive molecular profiling of both hematopoietic and stromal cell types at different from young and aged mice we have shown that increased TGF1 and IL-6 signalling 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.
Bi-directional c-Kit–mKitL signalling in hematopoiesis and breast cancer:
We previously identified bi-directional signalling by c-Kit and membrane-associated KitL (mKitL) as a novel signalling system that is critical for the post-natal expansion of the thymus (Buono et al., Nat. Cell Biol. 2016) and showed that it works by activating the AKT/mTOR pathway downstream of mKitL (Buono et al., Nat. Comms. 2018). Subsequently, we have shown that mKitL is expressed in a range of human cancers, and that signalling through mKitL is critical for triple-negative breast cancer progression.
Our next aim is to develop mKitL as a therapeutic target across multiple cancers, using genetic targeting in xenograft models of human cancer, and the development of first-in-class small-molecule mKitL inhibitors.
Projects are available in all these areas, including single cell analysis of human myeloid malignancies; the development of pharmacological strategies to counteract hematopoietic ageing; the identification of transcriptional and epigenetic mechanisms that specify normal and malignant HSC and progenitor cell populations; the role of ageing in development of myeloid malignancies; and the study of mKitL in human cancer models and development of mKitL small molecule inhibitors.
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