A5017274457- Acute Myeloid Leukemia Research
- Protein Degradation and Inhibitors
- Genomics and Chromatin Dynamics
- Epigenetics and DNA Methylation
- Histone Deacetylase Inhibitors Research
- Cancer-related gene regulation
- Acute Lymphoblastic Leukemia research
- Chronic Myeloid Leukemia Treatments
- Multiple Myeloma Research and Treatments
- Effects of Radiation Exposure
- Ubiquitin and proteasome pathways
- RNA Research and Splicing
- CAR-T cell therapy research
- RNA modifications and cancer
- Lymphoma Diagnosis and Treatment
- Chronic Lymphocytic Leukemia Research
- Single-cell and spatial transcriptomics
- Cancer Genomics and Diagnostics
- Genetic Mapping and Diversity in Plants and Animals
- RNA Interference and Gene Delivery
- Carcinogens and Genotoxicity Assessment
- Glutathione Transferases and Polymorphisms
- Phagocytosis and Immune Regulation
- Kruppel-like factors research
- CRISPR and Genetic Engineering
Wellcome/MRC Cambridge Stem Cell Institute
2016-2025
University of Cambridge
2016-2025
Medical Research Council
2015-2023
Wellcome Trust
2015-2020
Stem Cell Institute
2018-2020
Addenbrooke's Hospital
2011-2019
Institute for Medical Research
2011
University of Leicester
2006-2008
Recent evidence suggests that inhibition of bromodomain and extra-terminal (BET) epigenetic readers may have clinical utility against acute myeloid leukemia (AML). Here we validate this hypothesis, demonstrating the efficacy BET inhibitor I-BET151 across a variety AML subtypes driven by disparate mutations. We demonstrate common 'core' transcriptional program, which is HOX gene independent, downregulated in underlies sensitivity to I-BET treatment. This program enriched for genes contain...
Epigenetic regulators, such as EZH2, are frequently mutated in cancer, and loss-of-function EZH2 mutations common myeloid malignancies. We have examined the importance of cellular context for Ezh2 loss during evolution acute leukemia (AML), where we observed stage-specific diametrically opposite functions at early late stages disease. During disease maintenance, WT exerts an oncogenic function that may be therapeutically targeted. In contrast, acts a tumor suppressor AML induction....
DDX3X is a ubiquitously expressed RNA helicase involved in multiple stages of biogenesis. frequently mutated Burkitt lymphoma, but the functional basis for this unknown. Here, we show that loss-of-function mutations are also enriched MYC-translocated diffuse large B cell lymphoma and reveal cooperation between mutant MYC. promotes translation mRNA encoding components core translational machinery, thereby driving global protein synthesis. Loss-of-function moderate MYC-driven synthesis,...
The relationship between late normal tissue radiation injury phenotypes in 167 breast cancer patients treated with radiotherapy and: (i) dose (boost); (ii) an early acute reaction and (iii) genetic background was examined. Patients were genotyped at single nucleotide polymorphisms (SNPs) eight candidate genes. An to and/or the inheritance of transforming growth factor-β1 (TGFβ1 −509T) SNP contributed risk fibrosis. In contrast, additional 15 Gy electron boost X-ray repair cross-complementing...
Abstract Leukaemogenic mutations commonly disrupt cellular differentiation and/or enhance proliferation, thus perturbing the regulatory programs that control self-renewal and of stem progenitor cells. Translocations involving Mll1 ( Kmt2a ) gene generate powerful oncogenic fusion proteins, predominantly affecting infant paediatric AML ALL patients. The early stages leukaemogenic transformation are typically inaccessible from human patients conventional mouse models. Here, we take advantage...
Abstract Cellular differentiation requires extensive alterations in chromatin structure and function, which is elicited by the coordinated action of transcription factors. By contrast with factors, roles factors have not been systematically characterized. Here, we combine bulk ex vivo single-cell CRISPR screens to characterize role factor families hematopoiesis. We uncover marked lineage specificities for 142 revealing functional diversity among related (i.e. barrier-to-autointegration...
The accessibility of cell surface proteins makes them tractable for targeting by cancer immunotherapy, but identifying suitable targets remains challenging. Here we describe plasma membrane profiling primary human myeloma cells to identify an unprecedented number a cancer. We used novel approach prioritize immunotherapy and identified protein not previously implicated in myeloma, semaphorin-4A (SEMA4A). Using knock-down short-hairpin RNA CRISPR/nuclease-dead Cas9 (dCas9), show that...
Resistance to standard and novel therapies remains the main obstacle cure in acute myeloid leukaemia (AML) is often driven by metabolic adaptations which are therapeutically actionable. Here we identify inhibition of mannose-6-phosphate isomerase (MPI), first enzyme mannose metabolism pathway, as a sensitizer both cytarabine FLT3 inhibitors across multiple AML models. Mechanistically, connection between fatty acid metabolism, that mediated via preferential activation ATF6 arm unfolded...
Acute Myeloid Leukemia (AML) is an aggressive hematological malignancy with abnormal progenitor self-renewal and defective white blood cell differentiation. Its pathogenesis comprises subversion of transcriptional regulation, through mutation by hijacking normal chromatin regulation. Kat2a a histone acetyltransferase central to promoter activity, that we recently associated stability pluripotency networks, identified as genetic vulnerability in AML. Through combined profiling single-cell...
The introduction of highly selective ABL-tyrosine kinase inhibitors (TKIs) has revolutionized therapy for chronic myeloid leukemia (CML). However, TKIs are only efficacious in the phase disease and effective therapies TKI-refractory CML, or after progression to blast crisis (BC), lacking. Whereas CML is dependent on BCR-ABL, additional mutations required BC. identity these pathways they affect poorly understood, hampering our ability identify therapeutic targets improve outcomes. Here, we...
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...
Abstract Immunotherapies for acute myeloid leukemia (AML) and other cancers are limited by a lack of tumor-specific targets. Here we discover that RNA-binding proteins glycosylated RNAs (glycoRNAs) form precisely organized nanodomains on cancer cell surfaces. We characterize nucleophosmin (NPM1) as an abundant surface protein (csNPM1) variety tumor types. With focus AML, observe csNPM1 blasts leukemic stem cells but not normal hematopoietic cells. develop monoclonal antibody to target...