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2. How do Gata1 and cohesin gene mutations contribute to the development of myeloid leukaemia?

Author

Garnett, Catherine, Roberts, Irene, and Vyas, Paresh

Subjects
616.99
Abstract

Acute myeloid leukaemia (AML) is the most common aggressive human leukaemia. It is frequently characterised by the stepwise acquisition of multiple somatic mutations in stem and progenitor cells. The mechanisms by which these mutations interact to perturb normal cellular processes and drive transformation remains a key question in cancer biology. This thesis explores the co-operation between two mutations which commonly co-occur in an acute megakaryoblastic leukaemia unique to children with Down Syndrome: Gata1s and haploinsufficiency of the core cohesin component Rad21. Myeloid leukaemia of Down Syndrome (ML-DS) provides an excellent model in which to study multistep leukaemogenesis. It is biologically simpler than adult AML, comprising just three genetic events occurring in temporarily separable stages: (i) constitutive trisomy 21; (ii) an acquired truncating mutation in the transcription factor GATA1 (GATA1s) in fetal life, resulting in a preleukaemic condition, Transient Abnormal Myelopoiesis (TAM); (iii) additional somatic mutation(s) in the first 4 years of post natal life, transforming preleukaemic TAM clone(s) to ML-DS. Previous studies indicate that just one additional mutation in a cohesin complex gene may be sufficient for transformation, suggesting an important co-operative role. To address this, I first confirmed the co-existence of Gata1s and cohesin gene mutations in a large cohort of patient samples and characterised the frequency and predicted functional effect of these variants. I then explored the impact of these mutations, both alone and in combination, using a transgenic mouse model system. Combined Gata1s/cohesin mutant mice displayed a novel haematopoietic phenotype, characterised by expansion of the bone marrow megakaryocyte progenitor (MkP) compartment and abnormal differentiation and proliferation of the cells within it. Integrated molecular analysis of the MkP revealed altered gene expression profiles and chromatin accessibility, with dysregulation of a number of relevant transcription factor pathways. Significantly, both phenotypic and molecular analyses revealed a much greater effect of Gata1s plus cohesin haploinsufficiency than of either mutation alone, supporting a role for mutational co-operativity. The true nature of this interaction seems likely to be complex, potentially involving dysregulation of multiple targets and regulatory mechanisms within the cell.

Published
2019

3. Neonatal Leukemia

Author

Guest, Erin M., primary, Garnett, Catherine, additional, Roberts, Irene, additional, and Gamis, Alan S., additional

Published
2021
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4. Discovery of a CD10-negative B-progenitor in human fetal life identifies unique ontogeny-related developmental programs

Author

O'Byrne, Sorcha, Elliott, Natalina, Rice, Siobhan, Buck, Gemma, Fordham, Nicholas, Garnett, Catherine, Godfrey, Laura, Crump, Nicholas T., Wright, Gary, Inglott, Sarah, Hua, Peng, Psaila, Bethan, Povinelli, Benjamin, Knapp, David J.H.F., Agraz-Doblas, Antonio, Bueno, Clara, Varela, Ignacio, Bennett, Phillip, Koohy, Hashem, Watt, Suzanne M., Karadimitris, Anastasios, Mead, Adam J., Ancliff, Phillip, Vyas, Paresh, Menendez, Pablo, Milne, Thomas A., Roberts, Irene, and Roy, Anindita

Published
2019
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6. Improvement in mortality of hospitalized patients with hematological malignancies in the 2nd wave of COVID-19 in the UK: experience of a large London NHS trust

Author

Hinton, Richard, primary, Nesr, George, additional, Garnett, Catherine, additional, Foldes, David, additional, McCay, Joel James Robert, additional, Medland, Rachael, additional, Kagdi, Huseini, additional, Katsomitrou, Vaitsa, additional, Sim, Hau Wui, additional, Gandhi, Sameer, additional, Parcharidou, Agapi, additional, and Arami, Siamak, additional

Published
2021
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7. ITP flare with mild COVID‐19 infection in pregnancy: A case report

Author

Nesr, George, Garnett, Catherine, Bailey, Chris, and Arami, Siamak

Subjects
Adult, Purpura, Thrombocytopenic, Idiopathic, Letter, Platelet Count, SARS-CoV-2, viruses, Pneumonia, Viral, Pregnancy Complications, Hematologic, virus diseases, COVID-19, Betacoronavirus, Pregnancy, Humans, Female, Letters, Lymphocyte Count, Pregnancy Complications, Infectious, Coronavirus Infections, Pandemics
Abstract

Severe acute respiratory syndrome coronavirus‐2 (SARS‐CoV‐2) is the third zoonotic coronavirus to be identified in humans during the twenty‐first century, after severe acute respiratory syndrome coronavirus (SARS‐CoV) and Middle East respiratory syndrome coronavirus (MERS‐CoV)(Coronaviridae Study Group of the International Committee on Taxonomy,of Viruses, 2020). The resultant disease, Coronavirus Disease (COVID‐19) (WHO, 2020), was first identified in December 2019 in Wuhan, Hubei province, China (WHO, 2020) and rapidly evolved into a pandemic (WHO, 2020) within months. In the UK, the first confirmed case was identified in late January 2020 and the first COVID‐19 related death was recorded in March 2020 (UK Government, 2020).

Published
2020

8. Outcome of hospitalized patients with hematological malignancies and COVID-19 infection in a large urban healthcare trust in the United Kingdom

Author

Garnett, Catherine, primary, Foldes, David, additional, Bailey, Chris, additional, Nesr, George, additional, Hui, Tracy, additional, Hinton, Richard, additional, Gurung, Kamala, additional, Phillips, James, additional, Saleem, Zahbia, additional, Koshy, Rincy, additional, Aduwa, Elvis, additional, Colis, Marife, additional, Bimolah, Ravi, additional, Katsomitrou, Vaitsa, additional, Arami, Siamak, additional, and Kagdi, Huseini, additional

Published
2020
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11. Improvement in mortality of hospitalized patients with hematological malignancies in the 2nd wave of COVID-19 in the UK: experience of a large London NHS trust.

Author

Hinton, Richard, Nesr, George, Garnett, Catherine, Foldes, David, McCay, Joel James Robert, Medland, Rachael, Kagdi, Huseini, Katsomitrou, Vaitsa, Sim, Hau Wui, Gandhi, Sameer, Parcharidou, Agapi, and Arami, Siamak

Subjects
HEMATOLOGIC malignancies, HOSPITAL patients, HEART failure, LOW-molecular-weight heparin, PLASMA cell diseases
Abstract

In the second wave 57.8% (37/64) of patients received dexamethasone, 39.6% (25/64) of patients received remdesivir and one patient received tocilizumab. Patients with hematological malignancies who contract COVID-19 have been identified as having a high overall mortality rate of between 33 and 37% in a number of large studies from the first wave of COVID-19 infections in the first half of 2020 [[1], [3]]. In terms of hematological diagnoses, 34 patients had a lymphoid malignancy, 23 patients had a myeloid malignancy and 12 patients had a plasma cell disorder. Outcomes of patients with hematologic malignancies and COVID-19: a systematic review and meta-analysis of 3377 patients. [Extracted from the article]

Published
2022
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12. Discovery of a CD10-negative B-progenitor in human fetal life identifies unique ontogeny-related developmental programs

Author

O’Byrne, Sorcha, Elliott, Natalina, Rice, Siobhan, Buck, Gemma, Fordham, Nicholas, Garnett, Catherine, Godfrey, Laura, Crump, Nicholas T., Wright, Gary, Inglott, Sarah, Hua, Peng, Psaila, Bethan, Povinelli, Benjamin, Knapp, David J. H. F., Agraz-Doblas, Antonio, Bueno, Clara, Varela, Ignacio, Bennett, Phillip, Koohy, Hashem, Watt, Suzanne M., Karadimitris, Anastasios, Mead, Adam J., Ancliff, Phillip, Vyas, Paresh, Menéndez, Pablo, Milne, Thomas A., Roberts, Irene, Roy, Anindita, O’Byrne, Sorcha, Elliott, Natalina, Rice, Siobhan, Buck, Gemma, Fordham, Nicholas, Garnett, Catherine, Godfrey, Laura, Crump, Nicholas T., Wright, Gary, Inglott, Sarah, Hua, Peng, Psaila, Bethan, Povinelli, Benjamin, Knapp, David J. H. F., Agraz-Doblas, Antonio, Bueno, Clara, Varela, Ignacio, Bennett, Phillip, Koohy, Hashem, Watt, Suzanne M., Karadimitris, Anastasios, Mead, Adam J., Ancliff, Phillip, Vyas, Paresh, Menéndez, Pablo, Milne, Thomas A., Roberts, Irene, and Roy, Anindita

Abstract

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.

Published
2019

13. OncogenicGata1causes stage-specific megakaryocyte differentiation delay

Author

Juban, Gaëtan, primary, Sakakini, Nathalie, additional, Chagraoui, Hedia, additional, Cheng, Qian, additional, Soady, Kelly, additional, Stoilova, Bilyana, additional, Garnett, Catherine, additional, Waithe, Dominic, additional, Doondeea, Jess, additional, Usukhbayar, Batchimeg, additional, Karkoulia, Elena, additional, Alexiou, Maria, additional, Strouboulis, John, additional, Morrissey, Edward, additional, Roberts, Irene, additional, Porcher, Catherine, additional, and Vyas, Paresh, additional

Published
2019
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14. Mechanisms of Progression of Myeloid Preleukemia to Transformed Myeloid Leukemia in Children with Down Syndrome

Author

Labuhn, Maurice, primary, Perkins, Kelly, additional, Matzk, Sören, additional, Varghese, Leila, additional, Garnett, Catherine, additional, Papaemmanuil, Elli, additional, Metzner, Marlen, additional, Kennedy, Alison, additional, Amstislavskiy, Vyacheslav, additional, Risch, Thomas, additional, Bhayadia, Raj, additional, Samulowski, David, additional, Hernandez, David Cruz, additional, Stoilova, Bilyana, additional, Iotchkova, Valentina, additional, Oppermann, Udo, additional, Scheer, Carina, additional, Yoshida, Kenichi, additional, Schwarzer, Adrian, additional, Taub, Jeffrey W., additional, Crispino, John D., additional, Weiss, Mitchell J., additional, Hayashi, Yasuhide, additional, Taga, Takashi, additional, Ito, Etsuro, additional, Ogawa, Seishi, additional, Reinhardt, Dirk, additional, Yaspo, Marie-Laure, additional, Campbell, Peter J., additional, Roberts, Irene, additional, Constantinescu, Stefan N., additional, Vyas, Paresh, additional, Heckl, Dirk, additional, and Klusmann, Jan-Henning, additional

Published
2019
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15. Discovery of a CD10-negative B-progenitor in human fetal life identifies unique ontogeny-related developmental programs

Author

O’Byrne, Sorcha, primary, Elliott, Natalina, additional, Rice, Siobhan, additional, Buck, Gemma, additional, Fordham, Nicholas, additional, Garnett, Catherine, additional, Godfrey, Laura, additional, Crump, Nicholas T., additional, Wright, Gary, additional, Inglott, Sarah, additional, Hua, Peng, additional, Psaila, Bethan, additional, Povinelli, Benjamin, additional, Knapp, David J. H. F., additional, Agraz-Doblas, Antonio, additional, Bueno, Clara, additional, Varela, Ignacio, additional, Bennett, Phillip, additional, Koohy, Hashem, additional, Watt, Suzanne M., additional, Karadimitris, Anastasios, additional, Mead, Adam J., additional, Ancliff, Phillip, additional, Vyas, Paresh, additional, Menendez, Pablo, additional, Milne, Thomas A., additional, Roberts, Irene, additional, and Roy, Anindita, additional

Published
2019
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16. Modelling the Progression of a Preleukemic Stage to Overt Leukemia in Children with Down Syndrome

Author

Labuhn, Maurice, primary, Perkins, Kelly, additional, Papaemmanuil, Elli, additional, Garnett, Catherine, additional, Matzk, Soeren, additional, Amstislavskiy, Vyacheslav, additional, Metzner, Marlen, additional, Kennedy, Alison, additional, Scheer, Carina, additional, Yoshida, Kenichi, additional, Schwarzer, Adrian, additional, Crispino, John D., additional, Taub, Jeffrey W., additional, Weiss, Mitchell J., additional, Ito, Etsuro, additional, Ogawa, Seishi, additional, Reinhardt, Dirk, additional, Yaspo, Marie-Laure, additional, Campbell, Peter J., additional, Heckl, Dirk, additional, Klusmann, Jan-Henning, additional, and Vyas, Paresh, additional

Published
2018
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17. Outcome of hospitalized patients with hematological malignancies and COVID-19 infection in a large urban healthcare trust in the United Kingdom.

Author

Garnett, Catherine, Foldes, David, Bailey, Chris, Nesr, George, Hui, Tracy, Hinton, Richard, Gurung, Kamala, Phillips, James, Saleem, Zahbia, Koshy, Rincy, Aduwa, Elvis, Colis, Marife, Bimolah, Ravi, Katsomitrou, Vaitsa, Arami, Siamak, and Kagdi, Huseini

Subjects
*COVID-19, *MONOCLONAL gammopathies, *HOSPITAL patients, *MEDICAL care
Published
2021
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18. GATA1 and cooperating mutations in myeloid leukaemia of Down syndrome.

Author

Garnett, Catherine, Cruz Hernandez, David, and Vyas, Paresh

Subjects
*DOWN syndrome, *LEUKEMIA, *TRANSCRIPTION factors
Abstract

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. [ABSTRACT FROM AUTHOR]

Published
2020
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19. Mutational analysis of disease relapse in patients allografted for acute myeloid leukemia

Author

Quek, Lynn, primary, Ferguson, Paul, additional, Metzner, Marlen, additional, Ahmed, Ikhlaaq, additional, Kennedy, Alison, additional, Garnett, Catherine, additional, Jeffries, Sally, additional, Walter, Claudia, additional, Piechocki, Kim, additional, Timbs, Adele, additional, Danby, Robert, additional, Raghavan, Manoj, additional, Peniket, Andrew, additional, Griffiths, Mike, additional, Bacon, Andrew, additional, Ward, Janice, additional, Wheatley, Keith, additional, Vyas, Paresh, additional, and Craddock, Charles, additional

Published
2016
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20. Genetically distinct leukemic stem cells in human CD34− acute myeloid leukemia are arrested at a hemopoietic precursor-like stage

Author

Quek, Lynn, primary, Otto, Georg W., additional, Garnett, Catherine, additional, Lhermitte, Ludovic, additional, Karamitros, Dimitris, additional, Stoilova, Bilyana, additional, Lau, I-Jun, additional, Doondeea, Jessica, additional, Usukhbayar, Batchimeg, additional, Kennedy, Alison, additional, Metzner, Marlen, additional, Goardon, Nicolas, additional, Ivey, Adam, additional, Allen, Christopher, additional, Gale, Rosemary, additional, Davies, Benjamin, additional, Sternberg, Alexander, additional, Killick, Sally, additional, Hunter, Hannah, additional, Cahalin, Paul, additional, Price, Andrew, additional, Carr, Andrew, additional, Griffiths, Mike, additional, Virgo, Paul, additional, Mackinnon, Stephen, additional, Grimwade, David, additional, Freeman, Sylvie, additional, Russell, Nigel, additional, Craddock, Charles, additional, Mead, Adam, additional, Peniket, Andrew, additional, Porcher, Catherine, additional, and Vyas, Paresh, additional

Published
2016
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22. Functional and Genetic Heterogeneity of Distinct Leukemic Stem Cell Populations in CD34- Human Acute Myeloid Leukemia

Author

Quek, Lynn, primary, Otto, Georg, additional, Garnett, Catherine, additional, Lhermitte, Ludovic, additional, Lau, I-Jun, additional, Karamitros, Dimitris, additional, Doondeea, Jessica, additional, Usukhbayar, Batchimeg, additional, Goardon, Nicolas, additional, Ivey, Adam, additional, Gu, Yisu, additional, Allen, Christopher G, additional, Gale, Rosemary E, additional, Davies, Benjamin, additional, Sternberg, Alexander, additional, Killick, Sally, additional, Hunter, Hannah, additional, Cahalin, Paul, additional, Price, Andrew, additional, Carr, Andrew, additional, Griffiths, Mike, additional, Virgo, Paul, additional, Mackinnon, Stephen, additional, Grimwade, David, additional, Freeman, Sylvie D, additional, Russell, Nigel, additional, Craddock, Charles, additional, Mead, Adam, additional, Peniket, Andrew, additional, Porcher, Catherine, additional, and Vyas, Paresh, additional

Published
2014
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23. Impact of Mutant Haemopoietic Transcription Factor GATA1s on Haemopoiesis

Author

Vyas, Paresh, Juban, Gaetan, Sakakini, Nathalie, Soady, Kelly, Chagraoui, Hedia, Stoilova, Bilyana, Garnett, Catherine, Lhermitte, Ludovic, Karkoulia, Elena, Strouboulis, John, Porcher, Catherine, and Roberts, Irene

Abstract

Neonates and children with Down Syndrome (DS), with constitutional Trisomy 21 (T21), have a 150-fold increased risk of developing Myeloid Leukaemia (ML-DS), with differentiation arrest of immature megakaryocyte-erythroid cells. Virtually all ML-DS patients have in utero-acquired somatic mutations in the gene encoding the megakaryocyte-erythroid transcription factor GATA1 leading to the production of an 84 amino acid N-terminal truncated form of the GATA1 protein (GATA1s). We, and others, have previously shown that this N-terminal domain is necessary to prevent excessive megakaryocytic proliferation. However, the mechanisms by which GATA1, but not GATA1s, restrains megakaryocyte proliferation are unclear.

Published
2017
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24. Mature Analysis of the Prospective Oxford Down Syndrome (DS) Cohort Study: Timing and Clinical Impact of Preleukemic GATA1Mutations and Lessons for Management of Newborns with DS

Author

Roberts, Irene, Bhatnagar, Neha, Chaussade, Amelie, Nizery, Laure, Richmond, Helen, Elliott, Natalina, Buck, Gemma, Metzner, Marlen, Kennedy, Alison, Garnett, Catherine, Perkins, Kelly, and Vyas, Paresh

Abstract

Children with Down syndrome (DS) have a high risk of developing a unique form of AML known as myeloid leukaemia of DS (ML-DS) defined by the presence of one or more acquired N-terminal truncating mutations in the hematopoietic transcription factor gene GATA1. ML-DS is confined to children <4 y of age and preceded by a neonatal preleukemic syndrome, Transient Abnormal Myelopoiesis (TAM). Although the same GATA1mutations are present in ML-DS and TAM, indicating they are clonally-linked disorders, chemotherapy is essential to cure ML-DS whereas most cases of TAM spontaneously resolve without treatment.

Published
2017
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25. Oncogenic Gata1 causes stage-specific megakaryocyte differentiation delay.

Author

Juban G, Sakakini N, Chagraoui H, Cruz Hernandez D, Cheng Q, Soady K, Stoilova B, Garnett C, Waithe D, Otto G, Doondeea J, Usukhbayar B, Karkoulia E, Alexiou M, Strouboulis J, Morrissey E, Roberts I, Porcher C, and Vyas P

Subjects
Animals, Cell Differentiation, GATA1 Transcription Factor genetics, Humans, Infant, Newborn, Megakaryocytes, Mice, Down Syndrome, Leukemoid Reaction
Abstract

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.

Published
2021
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