A5035853507- Acute Myeloid Leukemia Research
- Myeloproliferative Neoplasms: Diagnosis and Treatment
- Chronic Myeloid Leukemia Treatments
- Histone Deacetylase Inhibitors Research
- Epigenetics and DNA Methylation
- Platelet Disorders and Treatments
- Cancer Genomics and Diagnostics
- Immune cells in cancer
- Hematopoietic Stem Cell Transplantation
- Cell Adhesion Molecules Research
- Blood disorders and treatments
- Protein Degradation and Inhibitors
- HIV/AIDS drug development and treatment
- Hemoglobinopathies and Related Disorders
- Blood properties and coagulation
- Immune Cell Function and Interaction
- Hematological disorders and diagnostics
- Multiple Myeloma Research and Treatments
- Cancer Research and Treatments
- Parvovirus B19 Infection Studies
- Prenatal Screening and Diagnostics
- Retinoids in leukemia and cellular processes
- Blood groups and transfusion
- Lung Cancer Treatments and Mutations
- Single-cell and spatial transcriptomics
King's College London
2009-2025
King's College Hospital NHS Foundation Trust
2020-2025
Blood Cancer UK
2022-2024
King's College Hospital
2008-2024
Oxford BioMedica (United Kingdom)
2019-2022
University of Oxford
2013-2022
Leuka
2022
MRC Weatherall Institute of Molecular Medicine
2012-2021
Medical Research Council
2013-2020
National Health Service
2016-2020
Risk stratification is critical in the care of patients with myelodysplastic syndromes (MDS). Approximately 10% have a complex karyotype (CK), defined as more than two cytogenetic abnormalities, which highly adverse prognostic marker. However, CK-MDS can carry wide range chromosomal abnormalities and somatic mutations. To refine risk patients, we examined data from 359 shared by International Working Group for MDS. Mutations were underrepresented exception TP53 mutations, identified 55%...
Abstract Isocitrate dehydrogenase (IDH) 1 and 2 mutations result in overproduction of D-2-hydroxyglutarate (2-HG) impaired cellular differentiation. Ivosidenib, a targeted mutant IDH1 (mIDH1) enzyme inhibitor, can restore normal differentiation results clinical responses subset patients with mIDH1 relapsed/refractory (R/R) acute myeloid leukemia (AML). We explored mechanisms ivosidenib resistance 174 confirmed R/R AML from phase trial. Receptor tyrosine kinase (RTK) pathway were associated...
Our understanding of the perturbation normal cellular differentiation hierarchies to create tumor-propagating stem cell populations is incomplete. In human acute myeloid leukemia (AML), current models suggest transformation creates leukemic (LSC) arrested at a progenitor-like stage expressing surface CD34. We show that in ∼25% AML, with distinct genetic mutation pattern where >98% cells are CD34(-), there multiple, nonhierarchically arranged CD34(+) and CD34(-) LSC populations. Within...
β-Thalassemia is one of the most common inherited anemias, with no effective cure for patients. The pathophysiology reflects an imbalance between α- and β-globin chains excess free α-globin causing ineffective erythropoiesis hemolysis. When α-thalassemia co-inherited β-thalassemia, are reduced significantly ameliorating clinical severity. Here we demonstrate use CRISPR/Cas9 genome editing primary human hematopoietic stem/progenitor (CD34+) cells to emulate a natural mutation, which deletes...
It is increasingly becoming clear that cancers are a symbiosis of diverse cell types and tumor clones. Combined single-cell RNA sequencing, flow cytometry, immunohistochemistry studies the innate immune compartment in bone marrow patients with acute myeloid leukemia (AML) reveal shift toward tumor-supportive M2-polarized macrophage landscape an altered transcriptional program, enhanced fatty acid oxidation NAD+ generation. Functionally, these AML-associated macrophages display decreased...
In the present study, we have addressed role of linker for activation T cells (LAT) in regulation phospholipase Cγ2 (PLCγ2) by platelet collagen receptor glycoprotein VI (GPVI). LAT is tyrosine phosphorylated human platelets heavily response to collagen, collagen-related peptide (CRP), and FcγRIIA cross-linking but only weakly G-protein-receptor-coupled agonist thrombin. phosphorylation abolished CRP-stimulated Syk-deficient mouse platelets, whereas it not altered SLP-76-deficient mice or...
Abstract Purpose: Azacitidine (AZA) is a novel therapeutic option in older patients with acute myeloid leukemia (AML), but its rational utilization compromised by the fact that neither determinants of clinical response nor mechanism action are defined. Co-administration histone deacetylase inhibitors, such as vorinostat (VOR), reported to improve activity AZA, this has not been prospectively studied AML. Experimental Design: We compared outcomes 259 adults AML (n = 217) and MDS 42)...
Disease relapse is the major cause of treatment failure after allogeneic stem cell transplantation (allo-SCT) in acute myeloid leukemia (AML). To identify AML-associated genes prognostic AML post-allo-SCT, we resequenced 35 113 adults at diagnosis, 49 whom relapsed. Two hundred sixty-two mutations were detected 102/113 (90%) patients. An increased risk was observed patients with WT1 (P = .018), DNMT3A .045), FLT3 ITD .071), and TP53 .06), whereas IDH1 associated a reduced disease .018). In...
Depleting the microenvironment of important nutrients such as arginine is a key strategy for immune evasion by cancer cells. Many tumors overexpress arginase, but it unclear how these cancers, not T cells, tolerate depletion. In this study, we show that tumor cells synthesize from citrulline upregulating argininosuccinate synthetase 1 (ASS1). Under starvation, ASS1 transcription induced ATF4 and CEBPβ binding to an enhancer within ASS1. cannot induce ASS1, despite presence active CEBPβ, gene...