A5025317732- Cancer-related gene regulation
- RNA Research and Splicing
- Genomics and Chromatin Dynamics
- Acute Myeloid Leukemia Research
- RNA modifications and cancer
- Acute Lymphoblastic Leukemia research
- Protein Degradation and Inhibitors
- Hematopoietic Stem Cell Transplantation
- Phagocytosis and Immune Regulation
- Immune responses and vaccinations
- Mesenchymal stem cell research
- Trace Elements in Health
- Growth Hormone and Insulin-like Growth Factors
- Ubiquitin and proteasome pathways
- Drug Transport and Resistance Mechanisms
- Immune cells in cancer
- Prion Diseases and Protein Misfolding
- Neurological diseases and metabolism
- Erythrocyte Function and Pathophysiology
- Chronic Lymphocytic Leukemia Research
- Epigenetics and DNA Methylation
University of Cambridge
2022-2024
Wellcome/MRC Cambridge Stem Cell Institute
2022-2024
Stem Cell Institute
2024
Medical Research Council
2023
European Bioinformatics Institute
2020
University College London
2011
Hematopoietic stem cells (HSCs) accumulate somatic mutations over time, some conferring a fitness advantage that can lead to clonal hematopoiesis (CH). Mutations in DNMT3A , particularly at hotspot R882, are the most prevalent CH and carry an increased risk of acute myeloid leukemia (AML). Although R882 linked global DNA hypomethylation, mechanisms underlying their selective remain unclear. Here, we show Dnmt3a-R882H mutant HSCs exhibit resilience under inflammatory genotoxic stress. During...
The introduction of novel CTCF binding sites in gene regulatory regions the rodent lineage is partly effect transposable element expansion, particularly murine lineage. exact mechanism and functional impact evolutionarily are not yet fully understood. We investigated subspecies-specific two Mus genus subspecies, musculus domesticus castaneus, that diverged 0.5 million years ago.CTCF site evolution influenced by action B2-B4 family elements independently both lineages, leading to...
Abstract B-cell acute lymphoblastic leukemia (B-ALL) is an aggressive hematological malignancy of B lineage progenitors. It remains a leading cause death in childhood, while outcomes adults are dismal. There therefore need to better understand drivers high-risk B-ALL and develop novel therapeutic approaches targeting these challenging patient cohorts. Loss-of-function mutations affecting CREBBP recurrent second-hit across multiple genetic subtypes associated with adverse features, including...
Abstract Loss-of-function mutations in the gene encoding acetyltransferase CREBBP have been reported numerous cancers but are particularly frequent lymphoid malignancies. However, functional significance of loss transformation and disease progression, most likely through cooperation with secondary genetic hits, has not yet fully unravelled. Similarly, contribution initial cell population sustaining course remains elusive. Here, we developed a new lymphoma mouse model integrating Crebbp at...
Abstract HOXA9 is commonly upregulated in acute myeloid leukemia (AML), where it confers poor prognosis. Characterising the protein interactome of endogenous human AML, we identified a chromatin complex with nuclear matrix attachment protein-SAFB. SAFB perturbation phenocopied knockout to decrease AML proliferation, increase differentiation and apoptosis vitro prolonged survival vivo . Integrated genomic, transcriptomic proteomic analyses further demonstrated that HOXA9-SAFB-chromatin...
Abstract B-cell acute lymphoblastic leukemia (B-ALL) is a leading cause of death in childhood and outcomes adults remain dismal. There therefore an urgent clinical need for therapies that target the highest risk cases. Mutations histone acetyltransferase CREBBP associate with high-risk features B-ALL have been implicated chemoresistance. We performed targeted drug screen isogenic human cell lines, identifying number actionable small molecules specifically -mutated B-ALL. The most potent was...
ABSTRACT The introduction of novel CTCF binding sites in gene regulatory regions the rodent lineage is partly effect transposable element expansion. exact mechanism and functional impact evolutionarily are not yet fully understood. We investigated species-specific two Mus genus subspecies, musculus domesticus castaneus, that diverged 0.5 million years ago. activity B2-B4 family elements independently both lineages leads to proliferation sites. A subset young may harbour transcriptional...