Publications by authors named "Catherine Garnett"

15 Publications

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Oncogenic Gata1 causes stage-specific megakaryocyte differentiation delay.

Haematologica 2021 04 1;106(4):1106-1119. Epub 2021 Apr 1.

MRC Molecular Haematology Unit WIMM, University of Oxford, UK.

The megakaryocyte/erythroid Transient Myeloproliferative Disorder (TMD) in newborns with Down Syndrome (DS) occurs when N-terminal truncating mutations of the hemopoietic transcription factor GATA1, that produce GATA1short protein (GATA1s), are acquired early in development. Prior work has shown that murine GATA1s, by itself, causes a transient yolk sac myeloproliferative disorder. However, it is unclear where in the hemopoietic cellular hierarchy GATA1s exerts its effects to produce this myeloproliferative state. Here, through a detailed examination of hemopoiesis from murine GATA1s ES cells and GATA1s embryos we define defects in erythroid and megakaryocytic differentiation that occur relatively late in hemopoiesis. GATA1s causes an arrest late in erythroid differentiation in vivo, and even more profoundly in ES-cell derived cultures, with a marked reduction of Ter-119 cells and reduced erythroid gene expression. In megakaryopoiesis, GATA1s causes a differentiation delay at a specific stage, with accumulation of immature, kit-expressing CD41hi megakaryocytic cells. In this specific megakaryocytic compartment, there are increased numbers of GATA1s cells in S-phase of cell cycle and reduced number of apoptotic cells compared to GATA1 cells in the same cell compartment. There is also a delay in maturation of these immature GATA1s megakaryocytic lineage cells compared to GATA1 cells at the same stage of differentiation. Finally, even when GATA1s megakaryocytic cells mature, they mature aberrantly with altered megakaryocyte-specific gene expression and activity of the mature megakaryocyte enzyme, acetylcholinesterase. These studies pinpoint the hemopoietic compartment where GATA1s megakaryocyte myeloproliferation occurs, defining where molecular studies should now be focussed to understand the oncogenic action of GATA1s.
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http://dx.doi.org/10.3324/haematol.2019.244541DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8018159PMC
April 2021

Immune thrombocytopenia flare with mild COVID-19 infection in pregnancy: A case report.

Br J Haematol 2020 08 30;190(3):e146-e148. Epub 2020 Jun 30.

Haematology Department, Northwick Park Hospital, UK.

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http://dx.doi.org/10.1111/bjh.16928DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7300661PMC
August 2020

GATA1 and cooperating mutations in myeloid leukaemia of Down syndrome.

IUBMB Life 2020 01 26;72(1):119-130. Epub 2019 Nov 26.

MRC Weatherall Institute of Molecular Medicine, University of Oxford, United Kingdom of Great Britain and Northern Ireland.

Myeloid leukaemia of Down syndrome (ML-DS) is an acute megakaryoblastic/erythroid leukaemia uniquely found in children with Down syndrome (constitutive trisomy 21). It has a unique clinical course, being preceded by a pre-leukaemic condition known as transient abnormal myelopoiesis (TAM), and provides an excellent model to study multistep leukaemogenesis. Both TAM and ML-DS blasts carry acquired N-terminal truncating mutations in the erythro-megakaryocytic transcription factor GATA1. These result in exclusive production of a shorter isoform (GATA1s). The majority of TAM cases resolve spontaneously without the need for treatment; however, around 10% acquire additional cooperating mutations and transform to leukaemia, with differentiation block and clinically significant cytopenias. Transformation is driven by the acquisition of additional mutation(s), which cooperate with GATA1s to perturb normal haematopoiesis.
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http://dx.doi.org/10.1002/iub.2197DOI Listing
January 2020

Discovery of a CD10-negative B-progenitor in human fetal life identifies unique ontogeny-related developmental programs.

Blood 2019 09 5;134(13):1059-1071. Epub 2019 Aug 5.

Department of Paediatrics and.

Human lymphopoiesis is a dynamic lifelong process that starts in utero 6 weeks postconception. Although fetal B-lymphopoiesis remains poorly defined, it is key to understanding leukemia initiation in early life. Here, we provide a comprehensive analysis of the human fetal B-cell developmental hierarchy. We report the presence in fetal tissues of 2 distinct CD19 B-progenitors, an adult-type CD10+ve ProB-progenitor and a new CD10-ve PreProB-progenitor, and describe their molecular and functional characteristics. PreProB-progenitors and ProB-progenitors appear early in the first trimester in embryonic liver, followed by a sustained second wave of B-progenitor development in fetal bone marrow (BM), where together they form >40% of the total hematopoietic stem cell/progenitor pool. Almost one-third of fetal B-progenitors are CD10-ve PreProB-progenitors, whereas, by contrast, PreProB-progenitors are almost undetectable (0.53% ± 0.24%) in adult BM. Single-cell transcriptomics and functional assays place fetal PreProB-progenitors upstream of ProB-progenitors, identifying them as the first B-lymphoid-restricted progenitor in human fetal life. Although fetal BM PreProB-progenitors and ProB-progenitors both give rise solely to B-lineage cells, they are transcriptionally distinct. As with their fetal counterparts, adult BM PreProB-progenitors give rise only to B-lineage cells in vitro and express the expected B-lineage gene expression program. However, fetal PreProB-progenitors display a distinct, ontogeny-related gene expression pattern that is not seen in adult PreProB-progenitors, and they share transcriptomic signatures with CD10-ve B-progenitor infant acute lymphoblastic leukemia blast cells. These data identify PreProB-progenitors as the earliest B-lymphoid-restricted progenitor in human fetal life and suggest that this fetal-restricted committed B-progenitor might provide a permissive cellular context for prenatal B-progenitor leukemia initiation.
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http://dx.doi.org/10.1182/blood.2019001289DOI Listing
September 2019

Mechanisms of Progression of Myeloid Preleukemia to Transformed Myeloid Leukemia in Children with Down Syndrome.

Cancer Cell 2019 08 11;36(2):123-138.e10. Epub 2019 Jul 11.

MRC MHU, BRC Hematology Theme, Oxford Biomedical Research Centre, Oxford Centre for Haematology, WIMM, Radcliffe Department of Medicine, University of Oxford, Oxford OX3 9DU, UK; Department of Paediatrics, University of Oxford, Oxford OX3 9DS, UK.

Myeloid leukemia in Down syndrome (ML-DS) clonally evolves from transient abnormal myelopoiesis (TAM), a preleukemic condition in DS newborns. To define mechanisms of leukemic transformation, we combined exome and targeted resequencing of 111 TAM and 141 ML-DS samples with functional analyses. TAM requires trisomy 21 and truncating mutations in GATA1; additional TAM variants are usually not pathogenic. By contrast, in ML-DS, clonal and subclonal variants are functionally required. We identified a recurrent and oncogenic hotspot gain-of-function mutation in myeloid cytokine receptor CSF2RB. By a multiplex CRISPR/Cas9 screen in an in vivo murine TAM model, we tested loss-of-function of 22 recurrently mutated ML-DS genes. Loss of 18 different genes produced leukemias that phenotypically, genetically, and transcriptionally mirrored ML-DS.
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http://dx.doi.org/10.1016/j.ccell.2019.06.007DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6863161PMC
August 2019

Mutational analysis of disease relapse in patients allografted for acute myeloid leukemia.

Blood Adv 2016 Dec 14;1(3):193-204. Epub 2016 Dec 14.

Centre for Clinical Haematology, Queen Elizabeth Hospital University Hospitals Birmingham NHS Foundation Trust, Birmingham, United Kingdom.

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 of AML relapse post-allo-SCT, we resequenced 35 genes in 113 adults at diagnosis, 49 of whom relapsed. Two hundred sixty-two mutations were detected in 102/113 (90%) patients. An increased risk of relapse was observed in patients with mutations in ( = .018), ( = .045), ( = .071), and ( = .06), whereas mutations in were associated with a reduced risk of disease relapse ( = .018). In 29 patients, we additionally compared mutational profiles in bone marrow at diagnosis and relapse to study changes in clonal structure at relapse. In 13/29 patients, mutational profiles altered at relapse. In 9 patients, mutations present at relapse were not detected at diagnosis. In 15 patients, additional available pre-allo-SCT samples demonstrated that mutations identified posttransplant but not at diagnosis were detectable immediately prior to transplant in 2 of 15 patients. Taken together, these observations, if confirmed in larger studies, have the potential to inform the design of novel strategies to reduce posttransplant relapse highlighting the potential importance of post-allo-SCT interventions with a broad antitumor specificity in contrast to targeted therapies based on mutational profile at diagnosis.
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http://dx.doi.org/10.1182/bloodadvances.2016000760DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5737177PMC
December 2016

Genetically distinct leukemic stem cells in human CD34- acute myeloid leukemia are arrested at a hemopoietic precursor-like stage.

J Exp Med 2016 07 4;213(8):1513-35. Epub 2016 Jul 4.

Medical Research Council, Molecular Hematology Unit, Weatherall Institute of Molecular Medicine, University of Oxford, Oxford OX1 2JD, England, UK Department of Hematology, Oxford University Hospital National Health Service Trust, Oxford OX3 9DU, England, UK.

Our understanding of the perturbation of 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 stem cell (LSC) populations arrested at a progenitor-like stage expressing cell surface CD34. We show that in ∼25% of AML, with a distinct genetic mutation pattern where >98% of cells are CD34(-), there are multiple, nonhierarchically arranged CD34(+) and CD34(-) LSC populations. Within CD34(-) and CD34(+) LSC-containing populations, LSC frequencies are similar; there are shared clonal structures and near-identical transcriptional signatures. CD34(-) LSCs have disordered global transcription profiles, but these profiles are enriched for transcriptional signatures of normal CD34(-) mature granulocyte-macrophage precursors, downstream of progenitors. But unlike mature precursors, LSCs express multiple normal stem cell transcriptional regulators previously implicated in LSC function. This suggests a new refined model of the relationship between LSCs and normal hemopoiesis in which the nature of genetic/epigenetic changes determines the disordered transcriptional program, resulting in LSC differentiation arrest at stages that are most like either progenitor or precursor stages of hemopoiesis.
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http://dx.doi.org/10.1084/jem.20151775DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC4986529PMC
July 2016

Treatment and management of graft-versus-host disease: improving response and survival.

Ther Adv Hematol 2013 Dec;4(6):366-78

Imperial College London at Hammersmith Hospital, London, UK.

Graft-versus-host disease (GVHD) is a significant cause of morbidity and mortality following allogenic haematopoietic stem-cell transplantation and thus the focus of much ongoing research. Despite considerable advances in our understanding of the pathophysiology, diagnosis and predisposing factors for both acute and chronic forms of the disease, a standardised therapeutic strategy is still lacking. There is good evidence for initial treatment of both acute and chronic forms of the disease with corticosteroid therapy. However, the most effective approach to steroid-refractory disease remains controversial, with current practice based mainly on smaller studies and varying considerably between local institutions. Timely diagnosis, multidisciplinary working and good supportive care, including infection prophylaxis, are clearly important in optimizing response and survival in such patients. It is hoped that in the future systematic research strategies and the identification of novel therapeutic targets may improve outcome further. The following review aims to outline some of the existing options for the treatment and management of acute and chronic GVHD.
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http://dx.doi.org/10.1177/2040620713489842DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC3854558PMC
December 2013

Dysplasia of all granulocyte lineages in myelodysplastic evolution of essential thrombocythemia.

Am J Hematol 2013 May 5;88(5):426. Epub 2013 Mar 5.

St. Mary's Hospital Campus of Imperial College, St. Mary's Hospital, Praed Street, London, W2 1NY, United Kingdom.

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http://dx.doi.org/10.1002/ajh.23395DOI Listing
May 2013

South-East Asian ovalocytosis.

Am J Hematol 2013 Apr 22;88(4):328. Epub 2013 Jan 22.

Department of Haematology, Imperial College Healthcare NHS Trust, St Mary's Hospital, Praed Street, London W2 1NY, United Kingdom.

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http://dx.doi.org/10.1002/ajh.23379DOI Listing
April 2013

Analysis of GATA1 mutations in Down syndrome transient myeloproliferative disorder and myeloid leukemia.

Blood 2011 Aug 29;118(8):2222-38. Epub 2011 Jun 29.

Molecular Haematology Unit, Weatherall Institute of Molecular Medicine, University of Oxford, John Radcliffe Hospital, Oxford, UK.

Children with Down syndrome (DS) up to the age of 4 years are at a 150-fold excess risk of developing myeloid leukemia (ML-DS). Approximately 4%-5% of newborns with DS develop transient myeloproliferative disorder (TMD). Blast cell structure and immunophenotype are similar in TMD and ML-DS. A mutation in the hematopoietic transcription factor GATA1 is present in almost all cases. Here, we show that simple techniques detect GATA1 mutations in the largest series of TMD (n = 134; 88%) and ML-DS (n = 103; 85%) cases tested. Furthermore, no significant difference in the mutational spectrum between the 2 disorders was seen. Thus, the type of GATA1 sequence mutation is not a reliable tool and is not prognostic of which patients with TMD are probable to develop ML-DS.
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http://dx.doi.org/10.1182/blood-2011-03-342774DOI Listing
August 2011

Recurrence of hyperprolactinaemia following discontinuation of dopamine agonist therapy in patients with prolactinoma occurs commonly especially in macroprolactinoma.

Clin Endocrinol (Oxf) 2011 Dec;75(6):819-24

Department of Endocrinology, Oxford Centre for Diabetes, Endocrinology and Metabolism, Churchill Hospital, Oxford OX3 7LJ, UK.

Context: The optimal duration of dopamine agonist (DA) therapy in prolactinoma is unknown. There are concerns that despite low recurrence rates in highly selected groups, high recurrence rates after DA withdrawal may occur in routine practice.

Objective: To explore recurrence of hyperprolactinaemia and predictive factors following DA withdrawal in patients with microprolactinoma and macroprolactinoma.

Design: A retrospective study on adult patients with confirmed prolactinoma attending the Oxford Endocrine Department.

Patients And Measurements: We identified patients with macroprolactinoma (n = 15) and microprolactinoma (n = 45) treated with DA therapy for >3 years, with a trial off DA therapy. None had other treatments. Measurements included recurrence of hyperprolactinaemia following DA withdrawal, tumour size (macroprolactinomas), duration of DA therapy, prolactin levels (baseline, during DA therapy, recurrence) and time to recurrence. Data were reported as mean (range).

Results: During DA therapy, prolactin levels suppressed to normal range in all patients with macroprolactinoma and microprolactinoma, and most macroprolactinomas (n = 14) had substantial tumour shrinkage. Hyperprolactinaemia recurred in 93% of macroprolactinomas (n = 14) at 8·8 months (3-36) and 64% of microprolactinomas (n = 29) at 4·8 months (3-12). Duration of DA therapy was 7·5 years (4-15) for macroprolactinomas and 4·1 years (3-10) for microprolactinomas. Prolactin levels during DA therapy were 144 mU/l (7-336) for macroprolactinomas and 278 mU/l (30-629) for microprolactinomas. For microprolactinomas, prolactin levels during DA therapy were less suppressed in those with recurrence than in those without recurrence (P < 0·05).

Conclusions: In routine practice, hyperprolactinaemia recurs early in most macroprolactinomas (93%) and microprolactinomas (64%) following DA therapy discontinuation. For most macroprolactinomas, cessation of DA cannot be recommended even after 7 years of therapy.
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http://dx.doi.org/10.1111/j.1365-2265.2011.04136.xDOI Listing
December 2011

Knockdown of SMN by RNA interference induces apoptosis in differentiated P19 neural stem cells.

Brain Res 2007 Dec 21;1183:1-9. Epub 2007 Sep 21.

Department of Physiology, Anatomy and Genetics, University of Oxford, South Parks Road, Oxford, OX1 3QX, UK.

Spinal muscular atrophy (SMA) is a common neurodegenerative disease that is caused by mutations in the survival of motor neuron gene (SMN), leading to reduced levels of the SMN protein in affected individuals. In SMA, motor neurons selectively degenerate, however, the mechanism of cell death and the precise role of SMN in this process are not completely understood. In this study, we apply RNA interference (RNAi) to knockdown Smn gene expression in the murine embryonal carcinoma stem cell line P19, which can be differentiated into neuronal cells. A direct effect of Smn loss on apoptotic cell death in differentiated P19 neuronal cells, and to a lesser extent in undifferentiated cells was observed. Apoptosis could be partly reversed by expression of an SMN rescue construct, was reversible by the addition of the caspase-inhibitor ZVAD-fmk and involved the cytochrome c pathway. This study shows for the first time that knockdown of SMN results in apoptosis in mammalian neuronal cells and has implications for understanding the cause of motor neuron-specific cell loss in SMA, and for identifying novel therapeutic targets for this disease.
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http://dx.doi.org/10.1016/j.brainres.2007.09.025DOI Listing
December 2007
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