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2. Model of the low temperature magnetic phases of gadolinium gallium garnet

Author

Ancliff, M., Sachnev, V., and d'Ambrumenil, N.

Subjects
Condensed Matter - Mesoscale and Nanoscale Physics, Condensed Matter - Materials Science
Abstract

The magnetic behaviour of gadolinium gallium garnet in an external magnetic field at zero temperature is considered. For high fields a classical spin model of the gadolinium ions predicts a spin configuration that is periodic at the level of the smallest repeating unit cell. The quantum version of the model is treated via a truncated Holstein-Primakoff transformation with axes defined by the classical spin configuration, and the magnon excitation bands are calculated. The model predicts a transition in the field range of $1.9$ -- $2.1\mathrm{T}$, sensitive to the direction of the applied field, which is caused by one or more magnon modes becoming soft as the field is decreased. In general the soft modes occur at incommensurate wavevectors and therefore break the periodicity of the spin configuration below the transition. One exception occurs when the field aligns with one of the principle crystal axes, in which case periodicity of the spin configuration is found to be maintained on a larger crystallographic cubic cell even below the transition. This simple case is studied in more detail. Comparisons are drawn with existing experimental data, and further experimental tests of the model are suggested., Comment: 15 pages, 10 figures

Published
2021
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3. Convergent somatic evolution commences in utero in a germline ribosomopathy

Author

Machado, Heather E., Øbro, Nina F., Williams, Nicholas, Tan, Shengjiang, Boukerrou, Ahmed Z., Davies, Megan, Belmonte, Miriam, Mitchell, Emily, Baxter, E. Joanna, Mende, Nicole, Clay, Anna, Ancliff, Philip, Köglmeier, Jutta, Killick, Sally B., Kulasekararaj, Austin, Meyer, Stefan, Laurenti, Elisa, Campbell, Peter J., Kent, David G., Nangalia, Jyoti, and Warren, Alan J.

Published
2023
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5. Convergent somatic evolution commences in utero in a germline ribosomopathy

Author

Heather E. Machado, Nina F. Øbro, Nicholas Williams, Shengjiang Tan, Ahmed Z. Boukerrou, Megan Davies, Miriam Belmonte, Emily Mitchell, E. Joanna Baxter, Nicole Mende, Anna Clay, Philip Ancliff, Jutta Köglmeier, Sally B. Killick, Austin Kulasekararaj, Stefan Meyer, Elisa Laurenti, Peter J. Campbell, David G. Kent, Jyoti Nangalia, and Alan J. Warren

Subjects
Science
Abstract

Abstract Clonal tracking of cells using somatic mutations permits exploration of clonal dynamics in human disease. Here, we perform whole genome sequencing of 323 haematopoietic colonies from 10 individuals with the inherited ribosomopathy Shwachman-Diamond syndrome to reconstruct haematopoietic phylogenies. In ~30% of colonies, we identify mutually exclusive mutations in TP53, EIF6, RPL5, RPL22, PRPF8, plus chromosome 7 and 15 aberrations that increase SBDS and EFL1 gene dosage, respectively. Target gene mutations commence in utero, resulting in a profusion of clonal expansions, with only a few haematopoietic stem cell lineages (mean 8, range 1-24) contributing ~50% of haematopoietic colonies across 8 individuals (range 4-100% clonality) by young adulthood. Rapid clonal expansion during disease transformation is associated with biallelic TP53 mutations and increased mutation burden. Our study highlights how convergent somatic mutation of the p53-dependent nucleolar surveillance pathway offsets the deleterious effects of germline ribosomopathy but increases opportunity for TP53-mutated cancer evolution.

Published
2023
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6. H3K79me2/3 controls enhancer–promoter interactions and activation of the pan-cancer stem cell marker PROM1/CD133 in MLL-AF4 leukemia cells

Author

Godfrey, Laura, Crump, Nicholas T, O’Byrne, Sorcha, Lau, I-Jun, Rice, Siobhan, Harman, Joe R, Jackson, Thomas, Elliott, Natalina, Buck, Gemma, Connor, Christopher, Thorne, Ross, Knapp, David JHF, Heidenreich, Olaf, Vyas, Paresh, Menendez, Pablo, Inglott, Sarah, Ancliff, Philip, Geng, Huimin, Roberts, Irene, Roy, Anindita, and Milne, Thomas A

Subjects
Biomedical and Clinical Sciences, Cardiovascular Medicine and Haematology, Clinical Sciences, Oncology and Carcinogenesis, Orphan Drug, Hematology, Pediatric Cancer, Stem Cell Research - Nonembryonic - Non-Human, Rare Diseases, Stem Cell Research, Cancer, Pediatric, Genetics, Aetiology, 2.1 Biological and endogenous factors, AC133 Antigen, Biomarkers, Tumor, Cell Line, Tumor, Cell Transformation, Neoplastic, Enhancer Elements, Genetic, Gene Expression Regulation, Leukemic, Gene Silencing, Histones, Humans, Immunophenotyping, Leukemia, Models, Biological, Myeloid-Lymphoid Leukemia Protein, Neoplastic Stem Cells, Oncogene Proteins, Fusion, Promoter Regions, Genetic, Protein Binding, Immunology, Cardiovascular medicine and haematology, Clinical sciences, Oncology and carcinogenesis
Abstract

MLL gene rearrangements (MLLr) are a common cause of aggressive, incurable acute lymphoblastic leukemias (ALL) in infants and children, most of which originate in utero. The most common MLLr produces an MLL-AF4 fusion protein. MLL-AF4 promotes leukemogenesis by activating key target genes, mainly through recruitment of DOT1L and increased histone H3 lysine-79 methylation (H3K79me2/3). One key MLL-AF4 target gene is PROM1, which encodes CD133 (Prominin-1). CD133 is a pentaspan transmembrane glycoprotein that represents a potential pan-cancer target as it is found on multiple cancer stem cells. Here we demonstrate that aberrant PROM1/CD133 expression is essential for leukemic cell growth, mediated by direct binding of MLL-AF4. Activation is controlled by an intragenic H3K79me2/3 enhancer element (KEE) leading to increased enhancer-promoter interactions between PROM1 and the nearby gene TAPT1. This dual locus regulation is reflected in a strong correlation of expression in leukemia. We find that in PROM1/CD133 non-expressing cells, the PROM1 locus is repressed by polycomb repressive complex 2 (PRC2) binding, associated with reduced expression of TAPT1, partially due to loss of interactions with the PROM1 locus. Together, these results provide the first detailed analysis of PROM1/CD133 regulation that explains CD133 expression in MLLr ALL.

Published
2021

8. A human fetal liver-derived infant MLL-AF4 acute lymphoblastic leukemia model reveals a distinct fetal gene expression program

Author

Siobhan Rice, Thomas Jackson, Nicholas T. Crump, Nicholas Fordham, Natalina Elliott, Sorcha O’Byrne, Maria del Mar Lara Fanego, Dilys Addy, Trisevgeni Crabb, Carryl Dryden, Sarah Inglott, Dariusz Ladon, Gary Wright, Jack Bartram, Philip Ancliff, Adam J. Mead, Christina Halsey, Irene Roberts, Thomas A. Milne, and Anindita Roy

Subjects
Science
Abstract

It is unknown why infant acute lymphoblastic leukemia (ALL) produced by MLL rearrangements leads to worse outcomes than childhood ALL. Here the authors develop a CRISPR-Cas9-induced human xenograft model of MLL-AF4 infant-ALL that faithfully replicates the disease and reveals that fetal-specific genes are potential infant-ALL drivers.

Published
2021
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9. Distribution of the transfer matrix in disordered wires

Author

Ancliff, Mark

Subjects
Condensed Matter - Mesoscale and Nanoscale Physics, Mathematical Physics
Abstract

A closed expression is derived for the probability distribution of the transfer matrix of a particle moving in a one-dimensional system with delta-correlated, weak disorder. The change in the distribution as a function of wire length is described by a diffusion equation on the $SU(1,1)$ group, which is solved through the decomposition of the regular representation into irreducible components. The expression generalizes a number of well-known results, including the distributions of the transmission coefficient and local density of states. As an application, the average single energy-level contribution to the persistent current in a flux-threaded ring is derived., Comment: 17 pages, 2 figures

Published
2016
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10. A human fetal liver-derived infant MLL-AF4 acute lymphoblastic leukemia model reveals a distinct fetal gene expression program

Author

Rice, Siobhan, Jackson, Thomas, Crump, Nicholas T., Fordham, Nicholas, Elliott, Natalina, O’Byrne, Sorcha, Fanego, Maria del Mar Lara, Addy, Dilys, Crabb, Trisevgeni, Dryden, Carryl, Inglott, Sarah, Ladon, Dariusz, Wright, Gary, Bartram, Jack, Ancliff, Philip, Mead, Adam J., Halsey, Christina, Roberts, Irene, Milne, Thomas A., and Roy, Anindita

Published
2021
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11. A minimal approach for the local statistical properties of a one-dimensional disordered wire

Author

Ancliff, M. and Muzykantskii, B. A.

Subjects
Condensed Matter - Mesoscale and Nanoscale Physics
Abstract

We consider a one-dimensional wire in gaussian random potential. By treating the spatial direction as imaginary time, we construct a `minimal' zero-dimensional quantum system such that the local statistical properties of the wire are given as products of statistically independent matrix elements of the evolution operator of the system. The space of states of this quantum system is found to be a particular non-unitary, infinite dimensional representation of the pseudo-unitary group, U(1,1). We show that our construction is minimal in a well defined sense, and compare it to the supersymmetry and Berezinskii techniques., Comment: 10 pages, 0 figures

Published
2005
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12. Squamous cell carcinoma in a child with Clericuzio‐type poikiloderma with neutropenia

Author

Rodgers, W, Ancliff, P, Ponting, CP, Sanchez‐Pulido, L, Burns, S, Hayman, M, Kimonis, V, Sebire, N, Bulstrode, N, and Harper, JI

Subjects
Carcinoma, Squamous Cell, Child, Female, Foot Diseases, Humans, Neutropenia, Neutrophils, Skin Abnormalities, Skin Neoplasms, Toes, Clinical Sciences, Oncology and Carcinogenesis, Dermatology & Venereal Diseases
Published
2013

14. MECOM-associated syndrome: a heterogeneous inherited bone marrow failure syndrome with amegakaryocytic thrombocytopenia

Author

Manuela Germeshausen, Phil Ancliff, Jaime Estrada, Markus Metzler, Eva Ponstingl, Horst Rütschle, Dirk Schwabe, Richard H. Scott, Sule Unal, Angela Wawer, Bernward Zeller, and Matthias Ballmaier

Subjects
Specialties of internal medicine, RC581-951
Abstract

Abstract: Heterozygous mutations in MECOM (MDS1 and EVI1 complex locus) have been reported to be causative of a rare association of congenital amegakaryocytic thrombocytopenia and radioulnar synostosis. Here we report on 12 patients with congenital hypomegakaryocytic thrombocytopenia caused by MECOM mutations (including 10 novel mutations). The mutations affected different functional domains of the EVI1 protein. The spectrum of phenotypes was much broader than initially reported for the first 3 patients; we found familial as well as sporadic cases, and the clinical spectrum ranged from isolated radioulnar synostosis with no or mild hematological involvement to severe bone marrow failure without obvious skeletal abnormality. The clinical picture included radioulnar synostosis, bone marrow failure, clinodactyly, cardiac and renal malformations, B-cell deficiency, and presenile hearing loss. No single clinical manifestation was detected in all patients affected by MECOM mutations. Radioulnar synostosis and B-cell deficiency were observed only in patients with mutations affecting a short region in the C-terminal zinc finger domain of EVI1. We propose the term MECOM-associated syndrome for this heterogeneous hereditary disease and inclusion of MECOM sequencing in the diagnostic workup of congenital bone marrow failure.

Published
2018
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15. Durable remissions in TCF3-HLF positive acute lymphoblastic leukemia with blinatumomab and stem cell transplantation

Author

Brice Mouttet, Luciana Vinti, Philip Ancliff, Nicole Bodmer, Benoît Brethon, Gunnar Cario, Christiane Chen-Santel, Sarah Elitzur, Volkan Hazar, Joachim Kunz, Anja Möricke, Jerry Stein, Ajay Vora, Yöntem Yaman, Martin Schrappe, Sema Anak, André Baruche, Franco Locatelli, Arend von Stackelberg, Martin Stanulla, and Jean-Pierre Bourquin

Subjects
Diseases of the blood and blood-forming organs, RC633-647.5
Published
2019
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16. Benefits for children with suspected cancer from routine whole-genome sequencing

Author

Hodder, Angus, Leiter, Sarah M., Kennedy, Jonathan, Addy, Dilys, Ahmed, Munaza, Ajithkumar, Thankamma, Allinson, Kieren, Ancliff, Phil, Bailey, Shivani, Barnard, Gemma, Burke, G. A. Amos, Burns, Charlotte, Cano-Flanagan, Julian, Chalker, Jane, Coleman, Nicholas, Cheng, Danny, Clinch, Yasmin, Dryden, Caryl, Ghorashian, Sara, Griffin, Blanche, Horan, Gail, Hubank, Michael, May, Phillippa, McDerra, Joanna, Nagrecha, Rajvi, Nicholson, James, O’Connor, David, Pavasovic, Vesna, Quaegebeur, Annelies, Rao, Anupama, Roberts, Thomas, Samarasinghe, Sujith, Stasevich, Iryna, Tadross, John A., Trayers, Claire, Trotman, Jamie, Vora, Ajay, Watkins, James, Chitty, Lyn S., Bowdin, Sarah, Armstrong, Ruth, Murray, Matthew J., Hook, Catherine E., Tarpey, Patrick, Vedi, Aditi, Bartram, Jack, and Behjati, Sam

Abstract

Clinical whole-genome sequencing (WGS) has been shown to deliver potential benefits to children with cancer and to alter treatment in high-risk patient groups. It remains unknown whether offering WGS to every child with suspected cancer can change patient management. We collected WGS variant calls and clinical and diagnostic information from 281 children (282 tumors) across two English units (n= 152 from a hematology center, n= 130 from a solid tumor center) where WGS had become a routine test. Our key finding was that variants uniquely attributable to WGS changed the management in ~7% (20 out of 282) of cases while providing additional disease-relevant findings, beyond standard-of-care molecular tests, in 108 instances for 83 (29%) cases. Furthermore, WGS faithfully reproduced every standard-of-care molecular test (n= 738) and revealed several previously unknown genomic features of childhood tumors. We show that WGS can be delivered as part of routine clinical care to children with suspected cancer and can change clinical management by delivering unexpected genomic insights. Our experience portrays WGS as a clinically impactful assay for routine practice, providing opportunities for assay consolidation and for delivery of molecularly informed patient care.

Published
2024
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18. Chemotherapy induces canalization of cell state in childhood B-cell precursor acute lymphoblastic leukemia

Author

Turati, V, Guerra-Assuncao, J, Potter, N, Gupta, R, Ecker, S, Daneviciute, A, Tarabichi, M, Webster, A, Ding, C, May, G, James, C, Brown, J, Conde, L, Russell, L, Ancliff, P, Inglott, S, Cazzaniga, G, Biondi, A, Hall, G, Lynch, M, Hubank, M, Macaulay, I, Beck, S, Van Loo, P, Jacobsen, S, Greaves, M, Herrero, J, Enver, T, Turati V. A., Guerra-Assuncao J. A., Potter N. E., Gupta R., Ecker S., Daneviciute A., Tarabichi M., Webster A. P., Ding C., May G., James C., Brown J., Conde L., Russell L. J., Ancliff P., Inglott S., Cazzaniga G., Biondi A., Hall G. W., Lynch M., Hubank M., Macaulay I., Beck S., Van Loo P., Jacobsen S. E., Greaves M., Herrero J., Enver T., Turati, V, Guerra-Assuncao, J, Potter, N, Gupta, R, Ecker, S, Daneviciute, A, Tarabichi, M, Webster, A, Ding, C, May, G, James, C, Brown, J, Conde, L, Russell, L, Ancliff, P, Inglott, S, Cazzaniga, G, Biondi, A, Hall, G, Lynch, M, Hubank, M, Macaulay, I, Beck, S, Van Loo, P, Jacobsen, S, Greaves, M, Herrero, J, Enver, T, Turati V. A., Guerra-Assuncao J. A., Potter N. E., Gupta R., Ecker S., Daneviciute A., Tarabichi M., Webster A. P., Ding C., May G., James C., Brown J., Conde L., Russell L. J., Ancliff P., Inglott S., Cazzaniga G., Biondi A., Hall G. W., Lynch M., Hubank M., Macaulay I., Beck S., Van Loo P., Jacobsen S. E., Greaves M., Herrero J., and Enver T.

Abstract

Comparison of intratumor genetic heterogeneity in cancer at diagnosis and relapse suggests that chemotherapy induces bottleneck selection of subclonal genotypes. However, evolutionary events subsequent to chemotherapy could also explain changes in clonal dominance seen at relapse. We therefore investigated the mechanisms of selection in childhood B-cell precursor acute lymphoblastic leukemia (BCP-ALL) during induction chemotherapy where maximal cytoreduction occurs. To distinguish stochastic versus deterministic events, individual leukemias were transplanted into multiple xenografts and chemotherapy administered. Analyses of the immediate post-treatment leukemic residuum at single-cell resolution revealed that chemotherapy has little impact on genetic heterogeneity. Rather, it acts on extensive, previously unappreciated, transcriptional and epigenetic heterogeneity in BCP-ALL, dramatically reducing the spectrum of cell states represented, leaving a genetically polyclonal but phenotypically uniform population, with hallmark signatures relating to developmental stage, cell cycle and metabolism. Hence, canalization of the cell state accounts for a significant component of bottleneck selection during induction chemotherapy.

Published
2021

20. H3K79me2/3 controls enhancer–promoter interactions and activation of the pan-cancer stem cell marker PROM1/CD133 in MLL-AF4 leukemia cells

Author

Godfrey, L., Crump, N. T., O'Byrne, S., Lau, I. J., Rice, S., Harman, J. R., Jackson, T., Elliott, N., Buck, G., Connor, C., Thorne, R., Knapp, D. J. H. F., Heidenreich, O., Vyas, P., Menéndez, Pablo, Inglott, S., Ancliff, P., Geng, H., Roberts, I., Roy, A., Milne, T. A., and Universitat Autònoma de Barcelona

Subjects
Cancer Research, Oncogene Proteins, Fusion, Stem cell marker, Cell Transformation, Histones, Models, hemic and lymphatic diseases, Cancer genomics, 2.1 Biological and endogenous factors, AC133 Antigen, Aetiology, Promoter Regions, Genetic, Cancer, Oncogene Proteins, Leukemic, Pediatric, Tumor, Leukemia, biology, Gene Expression Regulation, Leukemic, Hematology, Cell biology, Cell Transformation, Neoplastic, Enhancer Elements, Genetic, Oncology, Neoplastic Stem Cells, Stem Cell Research - Nonembryonic - Non-Human, Stem cell, PRC2, Myeloid-Lymphoid Leukemia Protein, Protein Binding, Enhancer Elements, Pediatric Cancer, Clinical Sciences, Oncology and Carcinogenesis, Immunology, Locus (genetics), Models, Biological, Article, Cell Line, Immunophenotyping, Promoter Regions, Histone H3, Rare Diseases, Genetic, Cell Line, Tumor, Genetics, Biomarkers, Tumor, Humans, Gene Silencing, Enhancer, Fusion, Gene, neoplasms, Neoplastic, Acute lymphocytic leukaemia, DOT1L, Biological, Stem Cell Research, Orphan Drug, Gene Expression Regulation, biology.protein, Biomarkers
Abstract

Altres ajuts: Acknowledgements TAM, LG, NTC, I-JL, RT, JRH, and SR were funded by Medical Research Council (MRC, UK) Molecular Haematology Unit grant MC_UU_12009/6, MC_UU_00016/6, and MR/ M003221/1. AR was supported by a Bloodwise Clinician Scientist Fellowship (grants: 14041 and 17001), Wellcome Trust Clinical Research Career Development Fellowship (216632/Z/19/Z), Lady Tata Memorial International Fellowship, and EHA-ASH Translational Research Training in Hematology Fellowship. SOB was funded by the Department of Paediatrics and Alexander Thatte Fund, University of Oxford. DJHFK is funded by a CIHR Postdoctoral Fellowship. IR is supported by the NIHR Oxford BRC, by a Bloodwise Program Grant (13001) and by the MRC Molecular Haematology Unit (MC_UU_12009/14). PV via the Molecular Haematology Unit (MC_UU_12009) and the National Institute for Health Research (NIHR) Oxford Biomedical Research Centre (BRC) Programme. We would like to acknowledge the WIMM Flow Cytometry Facility which is supported by the MRC HIU, MRC MHU (MC_UU_12009), NIHR Oxford BRC, Kay Kendall Leukemia Fund (KKL1057), John Fell Fund (131/030 and 101/517), the EPA fund (CF182 and CF170), and by the WIMM Strategic Alliance awards G0902418 and MC_UU_12025. We thank the High-Throughput Genomics Group at the Wellcome Trust Centre for Human Genetics (funded by Wellcome Trust Grant Reference 090532/Z/09/Z); the MRC WIMM Centre for Computational Biology (CCB), Radcliffe Department of Medicine, University of Oxford; and Jelena Telenius for the use of her pipelines. B-ALL work in PM's lab is financially supported by [...], the Fundación Uno entre Cienmil, the Fundación Leo Messi. PM also acknowledges structural support from the Obra Social La Caixa-Fundaciò Josep Carreras. The human fetal material was provided by the Joint MRC/ Wellcome Trust Grant 099175/Z/ 12/Z Human Developmental Biology Resource (http://hdbr.org). We gratefully acknowledge the kind generosity of patients, their parents, and staff at Great Ormond Street Hospital, London. MLL gene rearrangements (MLLr) are a common cause of aggressive, incurable acute lymphoblastic leukemias (ALL) in infants and children, most of which originate in utero. The most common MLLr produces an MLL-AF4 fusion protein. MLL-AF4 promotes leukemogenesis by activating key target genes, mainly through recruitment of DOT1L and increased histone H3 lysine-79 methylation (H3K79me2/3). One key MLL-AF4 target gene is PROM1, which encodes CD133 (Prominin-1). CD133 is a pentaspan transmembrane glycoprotein that represents a potential pan-cancer target as it is found on multiple cancer stem cells. Here we demonstrate that aberrant PROM1/CD133 expression is essential for leukemic cell growth, mediated by direct binding of MLL-AF4. Activation is controlled by an intragenic H3K79me2/3 enhancer element (KEE) leading to increased enhancer-promoter interactions between PROM1 and the nearby gene TAPT1. This dual locus regulation is reflected in a strong correlation of expression in leukemia. We find that in PROM1/CD133 non-expressing cells, the PROM1 locus is repressed by polycomb repressive complex 2 (PRC2) binding, associated with reduced expression of TAPT1, partially due to loss of interactions with the PROM1 locus. Together, these results provide the first detailed analysis of PROM1/CD133 regulation that explains CD133 expression in MLLr ALL.

Published
2020

21. Outcome of central nervous system relapses in childhood acute lymphoblastic leukaemia--prospective open cohort analyses of the ALLR3 trial.

Author

Ashish Narayan Masurekar, Catriona A Parker, Milensu Shanyinde, Anthony V Moorman, Jeremy P Hancock, Rosemary Sutton, Philip J Ancliff, Mary Morgan, Nicholas J Goulden, Chris Fraser, Peter M Hoogerbrugge, Tamas Revesz, Philip J Darbyshire, Shekhar Krishnan, Sharon B Love, and Vaskar Saha

Subjects
Medicine, Science
Abstract

The outcomes of Central Nervous System (CNS) relapses in children with acute lymphoblastic leukaemia (ALL) treated in the ALL R3 trial, between January 2003 and March 2011 were analysed. Patients were risk stratified, to receive a matched donor allogeneic transplant or fractionated cranial irradiation with continued treatment for two years. A randomisation of Idarubicin with Mitoxantrone closed in December 2007 in favour of Mitoxantrone. The estimated 3-year progression free survival for combined and isolated CNS disease were 40.6% (25·1, 55·6) and 38.0% (26.2, 49.7) respectively. Univariate analysis showed a significantly better survival for age

Published
2014
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23. Two patients with Hermansky Pudlak syndrome type 2 and novel mutations in AP3B1

Author

Matt Wenham, Samantha Grieve, Michelle Cummins, Matthew L. Jones, Sarah Booth, Rachel Kilner, Philip J. Ancliff, Gillian M. Griffiths, and Andrew D. Mumford

Subjects
Diseases of the blood and blood-forming organs, RC633-647.5
Abstract

Hermansky Pudlak syndrome type 2 (HPS2) is a rare disorder associated with mutations in the Adaptor Protein 3 (AP-3) complex, which is involved in sorting transmembrane proteins to lysosomes and related organelles. We now report 2 unrelated subjects with HPS2 who show a characteristic clinical phenotype of oculocutaneous albinism, platelet and T-lymphocyte dysfunction and neutropenia. The subjects were homozygous for different deletions within AP3B1 (g.del180242-180866, c.del153-156), which encodes the AP-3β3A subunit, resulting in frame shifts and introduction of nonsense substitutions (p.E693fsX13, p.E52fsX11). In the subject with p.E693fsX13, this resulted in expression of a truncated variant β3A protein. Cytotoxic T-lymphocyte (CTL) clones from both study subjects showed increased cell-surface expression of CD63 and reduced cytotoxicity. Platelets showed impaired aggregation and reduced uptake of 3H-serotonin. These findings are consistent with CTL granule and platelet dense granule defects, respectively. This report extends the clinical and laboratory description of HPS2.

Published
2010
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24. Germline selection shapes human mitochondrial DNA diversity

Author

Wei, W, Tuna, S, Keogh, MJ, Smith, KR, Aitman, TJ, Beales, PL, Bennett, DL, Gale, DP, Bitner-Glindzicz, MAK, Black, GC, Brennan, P, Elliott, P, Flinter, FA, Floto, RA, Houlden, H, Irving, M, Koziell, A, Maher, ER, Markus, HS, Morrell, NW, Newman, WG, Roberts, I, Sayer, JA, Smith, KGC, Taylor, JC, Watkins, H, Webster, AR, Wilkie, AOM, Williamson, C, Attwood, A, Brown, M, Brod, NC, Crisp-Hihn, A, Davis, J, Deevi, SVV, Dewhurst, EF, Edwards, K, Erwood, M, Fox, J, Frary, AJ, Hu, F, Jolley, J, Kingston, N, Linger, R, Mapeta, R, Martin, J, Meacham, S, Papadia, S, Rayner-Matthews, PJ, Samarghitean, C, Shamardina, O, Simeoni, I, Staines, S, Staples, E, Stark, H, Stephens, J, Titterton, C, Von Ziegenweidt, J, Watt, C, Whitehorn, D, Wood, Y, Yates, K, Yu, P, James, R, Ashford, S, Penkett, CJ, Stirrups, KE, Bariana, T, Lentaigne, C, Sivapalaratnam, S, Westbury, SK, Allsup, DJ, Bakchoul, T, Biss, T, Boyce, S, Collins, J, Collins, PW, Curry, NS, Downes, K, Dutt, T, Erber, WN, Evans, G, Everington, T, Favier, R, Gomez, K, Greene, D, Gresele, P, Hart, D, Kazmi, R, Kelly, AM, Lambert, M, Madan, B, Mangles, S, Mathias, M, Millar, C, Obaji, S, Peerlinck, K, Roughley, C, Schulman, S, Scully, M, Shapiro, SE, Sibson, K, Sims, MC, Tait, RC, Talks, K, Thys, C, Toh, C-H, Van Geet, C, Westwood, J-P, Mumford, AD, Ouwehand, WH, Freson, K, Laffan, MA, Tan, RYY, Harkness, K, Mehta, S, Muir, KW, Hassan, A, Traylor, M, Drazyk, AM, Parry, D, Ahmed, M, Kazkaz, H, Vandersteen, AM, Ormondroyd, E, Thomson, K, Dent, T, Buchan, RJ, Bueser, T, Carr-White, G, Cook, S, Daniels, MJ, Harper, AR, Ware, JS, Dixon, PH, Chambers, J, Cheng, F, Estiu, MC, Hague, WM, Marschall, H-U, Vazquez-Lopez, M, Arno, G, French, CE, Michaelides, M, Moore, AT, Sanchis-Juan, A, Carss, K, Raymond, FL, Chinnery, PF, Griffiths, P, Horvath, R, Hudson, G, Jurkute, N, Pyle, A, Yu-Wai-Man, P, Whitworth, J, Adlard, J, Armstrong, R, Brewer, C, Casey, R, Cole, TRP, Evans, DG, Greenhalgh, L, Hanson, HL, Hoffman, J, Izatt, L, Kumar, A, Lalloo, F, Ong, KR, Park, S-M, Searle, C, Side, L, Snape, K, Woodward, E, Tischkowitz, M, Grozeva, D, Kurian, MA, Themistocleous, AC, Gosal, D, Marshall, A, Matthews, E, McCarthy, MI, Renton, T, Rice, ASC, Vale, T, Walker, SM, Woods, CG, Thaventhiran, JE, Allen, HL, Savic, S, Alachkar, H, Antrobus, R, Baxendale, HE, Browning, MJ, Buckland, MS, Cooper, N, Edgar, JDM, Egner, W, Gilmour, KC, Goddard, S, Gordins, P, Grigoriadou, S, Hackett, S, Hague, R, Hayman, G, Herwadkar, A, Huissoon, AP, Jolles, S, Kelleher, P, Kumararatne, D, Longhurst, H, Lorenzo, LE, Lyons, PA, Maimaris, J, Noorani, S, Richter, A, Sargur, RB, Sewell, WAC, Thomas, D, Thomas, MJ, Worth, A, Yong, PFK, Kuijpers, TW, Thrasher, AJ, Levine, AP, Sadeghi-Alavijeh, O, Wong, EKS, Cook, HT, Chan, MMY, Hall, M, Harris, C, McAlinden, P, Marchbank, KJ, Marks, S, Maxwell, H, Mozere, M, Wessels, J, Johnson, SA, Bleda, M, Hadinnapola, C, Haimel, M, Swietlik, E, Bogaard, H, Church, C, Coghlan, G, Condliffe, R, Corris, P, Danesino, C, Eyries, M, Gall, H, Ghofrani, H-A, Gibbs, JSR, Girerd, B, Holden, S, Houweling, A, Howard, LS, Humbert, M, Kiely, DG, Kovacs, G, Lawrie, A, Ross, RVM, Moledina, S, Montani, D, Newnham, M, Olschewski, A, Olschewski, H, Peacock, A, Pepke-Zaba, J, Scelsi, L, Seeger, W, Soubrier, F, Suntharalingam, J, Toshner, M, Treacy, C, Trembath, R, Noordegraaf, AV, Waisfisz, Q, Wharton, J, Wilkins, MR, Wort, SJ, Graf, S, Louka, E, Roy, NB, Rao, A, Ancliff, P, Babbs, C, Layton, DM, Mead, AJ, O'Sullivan, J, Okoli, S, Saleem, M, Bierzynska, A, Diz, CB, Colby, E, Ekani, MN, Satchell, S, Fowler, T, Rendon, A, Scott, R, Smedley, D, Thomas, E, Caulfield, M, Abbs, S, Burrows, N, Chitre, M, Gattens, M, Gurnell, M, Kelsall, W, Poole, KES, Ross-Russell, R, Spasic-Boskovic, O, Twiss, P, Wagner, A, Banka, S, Clayton-Smith, J, Douzgou, S, Abulhoul, L, Aurora, P, Bockenhauer, D, Cleary, M, Dattani, M, Ganesan, V, Pilkington, C, Rahman, S, Shah, N, Wedderburn, L, Compton, CJ, Deshpande, C, Fassihi, H, Haque, E, Josifova, D, Mohammed, SN, Robert, L, Rose, SJ, Ruddy, DM, Sarkany, RN, Sayer, G, Shaw, AC, Campbell, C, Gibson, K, Koelling, N, Lester, T, Nemeth, AH, Palles, C, Patel, S, Sen, A, Taylor, J, Tomlinson, IP, Malka, S, Browning, AC, Burn, J, De Soyza, A, Graham, J, Pearce, S, Quinton, R, Schaefer, AM, Wilson, BT, Wright, M, Simpson, M, Syrris, P, Bradley, JR, Turro, E, ARD - Amsterdam Reproduction and Development, AII - Inflammatory diseases, Paediatric Infectious Diseases / Rheumatology / Immunology, Medical Research Council (MRC), Wellcome Trust, Wei, Wei [0000-0002-2945-3543], Tuna, Salih [0000-0003-3606-4367], Smith, Katherine R [0000-0002-0329-5938], Beales, Phil L [0000-0002-9164-9782], Bennett, David L [0000-0002-7996-2696], Gale, Daniel P [0000-0002-9170-1579], Brennan, Paul [0000-0003-1128-6254], Elliott, Perry [0000-0003-3383-3984], Floto, R Andres [0000-0002-2188-5659], Houlden, Henry [0000-0002-2866-7777], Koziell, Ania [0000-0003-4882-0246], Maher, Eamonn R [0000-0002-6226-6918], Markus, Hugh S [0000-0002-9794-5996], Morrell, Nicholas W [0000-0001-5700-9792], Newman, William G [0000-0002-6382-4678], Sayer, John A [0000-0003-1881-3782], Smith, Kenneth GC [0000-0003-3829-4326], Taylor, Jenny C [0000-0003-3602-5704], Watkins, Hugh [0000-0002-5287-9016], Webster, Andrew R [0000-0001-6915-9560], Wilkie, Andrew OM [0000-0002-2972-5481], Penkett, Christopher J [0000-0003-4006-7261], Stirrups, Kathleen E [0000-0002-6823-3252], Rendon, Augusto [0000-0001-8994-0039], Bradley, John R [0000-0002-7774-8805], Turro, Ernest [0000-0002-1820-6563], Chinnery, Patrick F [0000-0002-7065-6617], and Apollo - University of Cambridge Repository

Subjects
0301 basic medicine, Non-Mendelian inheritance, Genome, Mitochondrial/genetics, DNA, Mitochondrial/genetics, 0302 clinical medicine, Ovum/growth & development, MTDNA, TRANSCRIPTION, Genetics, education.field_of_study, Multidisciplinary, NIHR BioResource–Rare Diseases, ASSOCIATION, Heteroplasmy, Mitochondrial, Multidisciplinary Sciences, GENOME, REPLACEMENT, Science & Technology - Other Topics, Female, Maternal Inheritance, Mitochondrial DNA, General Science & Technology, Genetic genealogy, Population, Biology, Human mitochondrial genetics, SEQUENCE, DNA, Mitochondrial, 03 medical and health sciences, Genetic, 100,000 Genomes Project–Rare Diseases Pilot, Genetic variation, MD Multidisciplinary, Humans, Selection, Genetic, education, Selection, Ovum, Science & Technology, MUTATIONS, Genetic Variation, DNA, LEIGH-DISEASE, 030104 developmental biology, REPLICATION, Genome, Mitochondrial, HETEROPLASMY, 030217 neurology & neurosurgery
Abstract

INTRODUCTION Only 2.4% of the 16.5-kb mitochondrial DNA (mtDNA) genome shows homoplasmic variation at >1% frequency in humans. Migration patterns have contributed to geographic differences in the frequency of common genetic variants, but population genetic evidence indicates that selection shapes the evolving mtDNA phylogeny. The mechanism and timing of this process are not clear. Unlike the nuclear genome, mtDNA is maternally transmitted and there are many copies in each cell. Initially, a new genetic variant affects only a proportion of the mtDNA (heteroplasmy). During female germ cell development, a reduction in the amount of mtDNA per cell causes a “genetic bottleneck,” which leads to rapid segregation of mtDNA molecules and different levels of heteroplasmy between siblings. Although heteroplasmy is primarily governed by random genetic drift, there is evidence of selection occurring during this process in animals. Yet it has been difficult to demonstrate this convincingly in humans. RATIONALE To determine whether there is selection for or against heteroplasmic mtDNA variants during transmission, we studied 12,975 whole-genome sequences, including 1526 mother–offspring pairs of which 45.1% had heteroplasmy affecting >1% of mtDNA molecules. Harnessing both the mtDNA and nuclear genome sequences, we then determined whether the nuclear genetic background influenced mtDNA heteroplasmy, validating our findings in another 40,325 individuals. RESULTS Previously unknown mtDNA variants were less likely to be inherited than known variants, in which the level of heteroplasmy tended to increase on transmission. Variants in the ribosomal RNA genes were less likely to be transmitted, whereas variants in the noncoding displacement (D)–loop were more likely to be transmitted. MtDNA variants predicted to affect the protein sequence tended to have lower heteroplasmy levels than synonymous variants. In 12,975 individuals, we identified a correlation between the location of heteroplasmic sites and known D-loop polymorphisms, including the absence of variants in critical sites required for mtDNA transcription and replication. We defined 206 unrelated individuals for which the nuclear and mitochondrial genomes were from different human populations. In these individuals, new population-specific heteroplasmies were more likely to match the nuclear genetic ancestry than the mitochondrial genome on which the mutations occurred. These findings were independently replicated in 654 additional unrelated individuals. CONCLUSION The characteristics of mtDNA in the human population are shaped by selective forces acting on heteroplasmy within the female germ line and are influenced by the nuclear genetic background. The signature of selection can be seen over one generation, ensuring consistency between these two independent genetic systems.

Published
2019
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25. Impaired human hematopoiesis due to a cryptic intronic splicing mutation

Author

Abdulhay, N.J., Fiorini, C., Verboon, J.M., Ludwig, L.S., Ulirsch, J.C., Zieger, B., Lareau, C.A., Mi, X., Roy, A., Obeng, E.A., Erlacher, M., Gupta, N., Gabriel, S.B., Ebert, B.L., Niemeyer, C.M., Khoriaty, R.N., Ancliff, P., Gazda, H.T., Wlodarski, M.W., and Sankaran, V.G.

Subjects
Cancer Research
Abstract

Studies of allelic variation underlying genetic blood disorders have provided important insights into human hematopoiesis. Most often, the identified pathogenic mutations result in loss-of-function or missense changes. However, assessing the pathogenicity of noncoding variants can be challenging. Here, we characterize two unrelated patients with a distinct presentation of dyserythropoietic anemia and other impairments in hematopoiesis associated with an intronic mutation in GATA1 that is 24 nucleotides upstream of the canonical splice acceptor site. Functional studies demonstrate that this single-nucleotide alteration leads to reduced canonical splicing and increased use of an alternative splice acceptor site that causes a partial intron retention event. The resultant altered GATA1 contains a five-amino acid insertion at the C-terminus of the C-terminal zinc finger and has no observable activity. Collectively, our results demonstrate how altered splicing of GATA1, which reduces levels of the normal form of this master transcription factor, can result in distinct changes in human hematopoiesis.

Published
2019

26. Durable remissions in TCF3-HLF positive acute lymphoblastic leukemia with blinatumomab and stem cell transplantation

Author

Mouttet, B., Vinti, L., Ancliff, P., Bodmer, N., Brethon, B., Cario, G., Chen-Santel, C., Elitzur, S., Hazar, V., Kunz, J., Moricke, A., Stein, J., Vora, A., Yaman, Y., Schrappe, M., Anak, S., Baruchel, A., Locatelli, Franco, Stackelberg, A. V., Stanulla, M., Bourquin, J. -P., Locatelli F. (ORCID:0000-0002-7976-3654), Mouttet, B., Vinti, L., Ancliff, P., Bodmer, N., Brethon, B., Cario, G., Chen-Santel, C., Elitzur, S., Hazar, V., Kunz, J., Moricke, A., Stein, J., Vora, A., Yaman, Y., Schrappe, M., Anak, S., Baruchel, A., Locatelli, Franco, Stackelberg, A. V., Stanulla, M., Bourquin, J. -P., and Locatelli F. (ORCID:0000-0002-7976-3654)

Abstract

no abstract

Published
2019

28. Publisher Correction: Telomerecat: A ploidy-agnostic method for estimating telomere length from whole genome sequencing data

Author

Farmery, JHR, Smith, ML, Lynch, AG, Huissoon, A, Furnell, A, Mead, A, Levine, AP, Manzur, A, Thrasher, A, Greenhalgh, A, Parker, A, Sanchis-Juan, A, Richter, A, Gardham, A, Lawrie, A, Sohal, A, Creaser-Myers, A, Frary, A, Greinacher, A, Themistocleous, A, Peacock, AJ, Marshall, A, Mumford, A, Rice, A, Webster, A, Brady, A, Koziell, A, Manson, A, Chandra, A, Hensiek, A, In't Veld, AH, Maw, A, Kelly, AM, Moore, A, Noordegraaf, AV, Attwood, A, Herwadkar, A, Ghofrani, A, Houweling, AC, Girerd, B, Furie, B, Treacy, CM, Millar, CM, Sewell, C, Roughley, C, Titterton, C, Williamson, C, Hadinnapola, C, Deshpande, C, Toh, C-H, Bacchelli, C, Patch, C, Van Geet, C, Babbs, C, Bryson, C, Penkett, CJ, Rhodes, CJ, Watt, C, Bethune, C, Booth, C, Lentaigne, C, McJannet, C, Church, C, French, C, Samarghitean, C, Halmagyi, C, Gale, D, Greene, D, Hart, D, Allsup, D, Bennett, D, Edgar, D, Kiely, DG, Gosal, D, Perry, DJ, Keeling, D, Montani, D, Shipley, D, Whitehorn, D, Fletcher, D, Krishnakumar, D, Grozeva, D, Kumararatne, D, Thompson, D, Josifova, D, Maher, E, Wong, EKS, Murphy, E, Dewhurst, E, Louka, E, Rosser, E, Chalmers, E, Colby, E, Drewe, E, McDermott, E, Thomas, E, Staples, E, Clement, E, Matthews, E, Wakeling, E, Oksenhendler, E, Turro, E, Reid, E, Wassmer, E, Raymond, FL, Hu, F, Kennedy, F, Soubrier, F, Flinter, F, Kovacs, G, Polwarth, G, Ambegaonkar, G, Arno, G, Hudson, G, Woods, G, Coghlan, G, Hayman, G, Arumugakani, G, Schotte, G, Cook, HT, Alachkar, H, Allen, HL, Lango-Allen, H, Stark, H, Stauss, H, Schulze, H, Boggard, HJ, Baxendale, H, Dolling, H, Firth, H, Gall, H, Watson, H, Longhurst, H, Markus, HS, Watkins, H, Simeoni, I, Emmerson, I, Roberts, I, Quinti, I, Wanjiku, I, Gibbs, JSR, Thaventhiran, J, Whitworth, J, Hurst, J, Collins, J, Suntharalingam, J, Payne, J, Thachil, J, Martin, JM, Martin, J, Carmichael, J, Maimaris, J, Paterson, J, Pepke-Zaba, J, Heemskerk, JWM, Gebhart, J, Davis, J, Pasi, J, Bradley, JR, Wharton, J, Stephens, J, Rankin, J, Anderson, J, Vogt, J, Von Ziegenweldt, J, Rehnstrom, K, Megy, K, Talks, K, Peerlinck, K, Yates, K, Freson, K, Stirrups, K, Gomez, K, Smith, KGC, Carss, K, Rue-Albrecht, K, Gilmour, K, Masati, L, Scelsi, L, Southgate, L, Ranganathan, L, Ginsberg, L, Devlin, L, Willcocks, L, Ormondroyd, L, Lorenzo, L, Harper, L, Allen, L, Daugherty, L, Chitre, M, Kurian, M, Humbert, M, Tischkowitz, M, Bitner-Glindzicz, M, Erwood, M, Scully, M, Veltman, M, Caulfield, M, Layton, M, McCarthy, M, Ponsford, M, Toshner, M, Bleda, M, Wilkins, M, Mathias, M, Reilly, M, Afzal, M, Brown, M, Rondina, M, Stubbs, M, Haimel, M, Lees, M, Laffan, MA, Browning, M, Gattens, M, Richards, M, Michaelides, M, Lambert, MP, Makris, M, De Vries, M, Mahdi-Rogers, M, Saleem, M, Thomas, M, Holder, M, Eyries, M, Clements-Brod, N, Canham, N, Dormand, N, Van Zuydam, N, Kingston, N, Ghali, N, Cooper, N, Morrell, NW, Yeatman, N, Roy, N, Shamardina, O, Alavijeh, OS, Gresele, P, Nurden, P, Chinnery, P, Deegan, P, Yong, P, Yu-Wai-Man, P, Corris, PA, Calleja, P, Gissen, P, Bolton-Maggs, P, Rayner-Matthews, P, Ghataorhe, PK, Gordins, P, Stein, P, Collins, P, Dixon, P, Kelleher, P, Ancliff, P, Yu, P, Tait, RC, Linger, R, Doffinger, R, Machado, R, Kazmi, R, Sargur, R, Favier, R, Tan, R, Liesner, R, Antrobus, R, Sandford, R, Scott, R, Trembath, R, Horvath, R, Hadden, R, MackenzieRoss, RV, Henderson, R, MacLaren, R, James, R, Ghurye, R, DaCosta, R, Hague, R, Mapeta, R, Armstrong, R, Noorani, S, Murng, S, Santra, S, Tuna, S, Johnson, S, Chong, S, Lear, S, Walker, S, Goddard, S, Mangles, S, Westbury, S, Mehta, S, Hackett, S, Nejentsev, S, Moledina, S, Bibi, S, Meehan, S, Othman, S, Revel-Vilk, S, Holden, S, McGowan, S, Staines, S, Savic, S, Burns, S, Grigoriadou, S, Papadia, S, Ashford, S, Schulman, S, Ali, S, Park, S-M, Davies, S, Stock, S, Deevi, SVV, Graf, S, Ghio, S, Wort, SJ, Jolles, S, Austin, S, Welch, S, Meacham, S, Rankin, S, Seneviratne, S, Holder, S, Sivapalaratnam, S, Richardson, S, Kuijpers, T, Kuijpers, TW, Bariana, TK, Bakchoul, T, Everington, T, Renton, T, Young, T, Aitman, T, Warner, TQ, Vale, T, Hammerton, T, Pollock, V, Matser, V, Cookson, V, Clowes, V, Qasim, W, Wei, W, Erber, WN, Ouwehand, WH, Astle, W, Egner, W, Turek, W, Henskens, Y, Tan, Y, Lynch, Andy G [0000-0002-7876-7338], Apollo - University of Cambridge Repository, Medical Research Council (MRC), and British Heart Foundation

Subjects
Whole genome sequencing, 0303 health sciences, Multidisciplinary, Science & Technology, lcsh:R, lcsh:Medicine, Computational biology, Biology, Telomere, Multidisciplinary Sciences, 03 medical and health sciences, 0302 clinical medicine, NIHR BioResource - Rare Diseases, ComputingMethodologies_DOCUMENTANDTEXTPROCESSING, Science & Technology - Other Topics, lcsh:Q, Ploidy, lcsh:Science, 030217 neurology & neurosurgery, 030304 developmental biology
Abstract

Correction to: Scientific Reports https://doi.org/10.1038/s41598-017-14403-y, published online 22 January 2018 The original version of this Article contained a typographical error in the spelling of the consortium member Patrick Yu-Wai-Man which was incorrectly given as Patrick Yu Wai Man. In addition, a supplementary file containing additional algorithms and analysis was omitted from the original version of this Article. These errors have now been corrected in the HTML and PDF versions of the Article.

Published
2018

29. PS948 EXCELLENT RESPONSE TO BLINATUMOMAB IN REFRACTORY B LINEAGE ACUTE LYMPHOBLASTIC LEUKAEMIA IN CHILDREN AND YOUNG ADULTS AFTER DEBULKING CHEMOTHERAPY TO ACHIEVE PARTIAL REMISSION

Author

Clesham, K., primary, Rao, V., additional, Bartram, J., additional, Ancliff, P., additional, Ghorashian, S., additional, O’Connor, D., additional, Pavasovic, V., additional, Rao, A., additional, Samarasinghe, S., additional, Cummins, M., additional, Marks, D., additional, Taylor, G., additional, Nicholson, E., additional, Macartney, C., additional, Patrick, K., additional, Bonney, D., additional, Gibson, B., additional, and Vora, A., additional

Published
2019
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30. PF153 MLL-AF4 CAUSES ABERRANT UPREGULATION OF PROM1 (CD133) IN ACUTE LYMPHOBLASTIC LEUKEMIA BY CONTROLLING ENHANCER-PROMOTER INTERACTIONS

Author

Godfrey, L., primary, O’Byrne, S., additional, Crump, N.T., additional, Lau, I.-J., additional, Thorne, R., additional, Elliott, N., additional, Buck, G., additional, Rice, S., additional, Connor, C., additional, Thomas, R., additional, Cheng, D., additional, Ancliff, P., additional, Inglott, S., additional, Roberts, I., additional, Roy, A., additional, and Milne, T.A., additional

Published
2019
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31. G-CSF Vs Haematopoietic Stem Cell Transplantation in Severe Congenital Neutropenia with ELANE Mutation: Role of G-CSF Dose. a Retrospective Controlled Study on Behalf of Saawp (Severe Aplastic Anemia Working Party) of the EBMT, of the Stem Cell Transplant for Immunodeficiency Group in Europe (SCETIDE), of the Severe Chronic Neutropenia French Registry (SCNFR) and Italian Neutropenia Registry (INR)

Author

Fioredda, F, Pierri, F, Zanardi, S, Gaspar, B, Ancliff, P, Bierings, M, Ozturk, G, Smith, O, Veys, P, Ljungman, P, De Latour, Rp, Or, R, Wynn, R, Kalwak, K, Russo, G, Tucci, F, Knoll, Cm, Martire, B, Favre, C, Chantelot, Cb, Beaupain, B, Donadieu, J, and Dufour, C

Published
2017

32. Targeting acute myeloid leukemia by drug-induced c-MYB degradation

Author

Walf-Vorderwülbecke, V, primary, Pearce, K, additional, Brooks, T, additional, Hubank, M, additional, van den Heuvel-Eibrink, M M, additional, Zwaan, C M, additional, Adams, S, additional, Edwards, D, additional, Bartram, J, additional, Samarasinghe, S, additional, Ancliff, P, additional, Khwaja, A, additional, Goulden, N, additional, Williams, G, additional, de Boer, J, additional, and Williams, O, additional

Published
2017
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33. Stem cell transplantation in severe congenital neutropenia: An analysis from the European Society for Blood and Marrow Transplantation

Author

Fioredda, F., Iacobelli, S., Biezen, A. van, Gaspar, B., Ancliff, P., Donadieu, J., Aljurf, M., Peters, C., Calvillo, M., Matthes-Martin, S., Morreale, G., van't Veer-Tazelaar, N., Wreede, L. de, Seraihy, A. al, Yesilipek, A., Fischer, A., Bierings, M., Ozturk, G., Smith, O., Veys, P., Ljungman, P., Latour, R.P. de, Codina, J.S.D., Or, R., Ganser, A., Afanasyev, B., Wynn, R., Kalwak, K., Marsh, J., Dufour, C., Pediat Dis Working Parties Europea, Fioredda, Francesca, Iacobelli, Simona, Van Biezen, Anja, Gaspar, Bobby, and Risitano, ANTONIO MARIA

Subjects
Male, Graft Rejection, medicine.medical_treatment, Graft vs Host Disease, Hematopoietic stem cell transplantation, Biochemistry, Allograft, Retrospective Studie, Cumulative incidence, Non-U.S. Gov't, Child, Societies, Medical, Incidence (epidemiology), Research Support, Non-U.S. Gov't, Histocompatibility Testing, Incidence, Medicine (all), Hematopoietic Stem Cell Transplantation, Hematology, Allografts, Clinical Trial, Multicenter Study, Europe, surgical procedures, operative, Child, Preschool, Acute Disease, Cyclosporine, Female, Unrelated Donors, Kostmann syndrome, Human, Adult, medicine.medical_specialty, Neutropenia, Adolescent, Immunology, Research Support, Settore MED/01 - Statistica Medica, Middle East, Internal medicine, Medical, medicine, Journal Article, Humans, Aplastic anemia, Congenital Neutropenia, Preschool, Retrospective Studies, business.industry, Unrelated Donor, Cell Biology, medicine.disease, Surgery, Transplantation, Methotrexate, business, Societies
Abstract

Allogeneic hematopoietic stem cell transplantation (HSCT) is the only curative treatment of severe congenital neutropenia (SCN), but data on outcome are scarce. We report on the outcome of 136 SCN patients who underwent HSCT between 1990 and 2012 in European and Middle East centers. The 3-year overall survival (OS) was 82%, and transplant-related mortality (TRM) was 17%. In multivariate analysis, transplants performed under the age of 10 years, in recent years, and from HLA-matched related or unrelated donors were associated with a significantly better OS. Frequency of graft failure was 10%. Cumulative incidence (day +90) of acute graft-versus-host disease (GVHD) grade 2-4 was 21%. In multivariate analysis, HLA-matched related donor and prophylaxis with cyclosporine A and methotrexate were associated with lower occurrence of acute GVHD. Cumulative incidence (1 year) of chronic GVHD was 20%. No secondary malignancies occurred after a median follow-up of 4.6 years. These data show that the outcome of HSCT for SCN from HLA-matched donors, performed in recent years, in patients younger than 10 years is acceptable. Nevertheless, given the TRM, a careful selection of HSCT candidates should be undertaken.

Published
2015

35. Blinatumomab for infant acute lymphoblastic leukemia

Author

Clesham, Katherine, Rao, Vasudha, Bartram, Jack, Ancliff, Philip, Ghorashian, Sara, O’Connor, David, Pavasovic, Vesna, Rao, Anupama, Samarasinghe, Sujith, Cummins, Michelle, Malone, Andrea, Patrick, Katharine, Bonney, Denise, James, Beki, Gibson, Brenda, and Vora, Ajay

Published
2020
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36. Optimised molecular genetic diagnostics of Fanconi anaemia by whole exome sequencing and functional studies

Author

Bogliolo, Massimo, Pujol, Roser, Aza-Carmona, Miriam, Muñoz-Subirana, Núria, Rodriguez-Santiago, Benjamin, Casado, José Antonio, Rio, Paula, Bauser, Christopher, Reina-Castillón, Judith, Lopez-Sanchez, Marcos, Gonzalez-Quereda, Lidia, Gallano, Pia, Catalá, Albert, Ruiz-Llobet, Ana, Badell, Isabel, Diaz-Heredia, Cristina, Hladun, Raquel, Senent, Leonort, Argiles, Bienvenida, Bergua Burgues, Juan Miguel, Bañez, Fatima, Arrizabalaga, Beatriz, López Almaraz, Ricardo, Lopez, Monica, Figuera, Ángela, Molinés, Antonio, Pérez de Soto, Inmaculada, Hernando, Inés, Muñoz, Juan Antonio, del Rosario Marin, Maria, Balmaña, Judith, Stjepanovic, Neda, Carrasco, Estela, Cuesta, Isabel, Cosuelo, José Miguel, Regueiro, Alexandra, Moraleda Jimenez, José, Galera-Miñarro, Ana Maria, Rosiñol, Laura, Carrió, Anna, Beléndez-Bieler, Cristina, Escudero Soto, Antonio, Cela, Elena, de la Mata, Gregorio, Fernández-Delgado, Rafael, Garcia-Pardos, Maria Carmen, Sáez-Villaverde, Raquel, Barragaño, Marta, Portugal, Raquel, Lendinez, Francisco, Hernadez, Ines, Vagace, José Manue, Tapia, Maria, Nieto, José, Garcia, Marta, Gonzalez, Macarena, Vicho, Cristina, Galvez, Eva, Valiente, Alberto, Antelo, Maria Luisa, Ancliff, Phil, Garcia, Francisco, Dopazo, Joaquin, Sevilla, Julian, Paprotka, Tobias, Pérez-Jurado, Luis Alberto, Bueren, Juan, and Surralles, Jordi

Abstract

PurposePatients with Fanconi anaemia (FA), a rare DNA repair genetic disease, exhibit chromosome fragility, bone marrow failure, malformations and cancer susceptibility. FA molecular diagnosis is challenging since FA is caused by point mutations and large deletions in 22 genes following three heritability patterns. To optimise FA patients’ characterisation, we developed a simplified but effective methodology based on whole exome sequencing (WES) and functional studies.Methods68 patients with FA were analysed by commercial WES services. Copy number variations were evaluated by sequencing data analysis with RStudio. To test FANCAmissense variants, wt FANCA cDNA was cloned and variants were introduced by site-directed mutagenesis. Vectors were then tested for their ability to complement DNA repair defects of a FANCA-KO human cell line generated by TALEN technologies.ResultsWe identified 93.3% of mutated alleles including large deletions. We determined the pathogenicity of three FANCA missense variants and demonstrated that two FANCAvariants reported in mutations databases as ‘affecting functions’ are SNPs. Deep analysis of sequencing data revealed patients’ true mutations, highlighting the importance of functional analysis. In one patient, no pathogenic variant could be identified in any of the 22 known FA genes, and in seven patients, only one deleterious variant could be identified (three patients each with FANCA and FANCD2 and one patient with FANCE mutations)ConclusionWES and proper bioinformatics analysis are sufficient to effectively characterise patients with FA regardless of the rarity of their complementation group, type of mutations, mosaic condition and DNA source.

Published
2020
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37. Maintenance therapy for early loss of B-cell aplasia after anti-CD19 CAR T-cell therapy

Author

Gabelli, Maria, Oporto-Espuelas, Macarena, Burridge, Saskia, Chu, Jan, Farish, Susan, Hedges, Emma, Ware, Kirsty, Williams, Lindsey, Young, Lindsey, Alajangi, Rajesh, Ancliff, Philip, Bartram, Jack, Bonney, Denise, Chenchara, Lenka, Chiesa, Robert, Cugno, Chiara, Hodby, Katharine, Jalowiec, Katarzyna A., Lazareva, Arina, Lucchini, Giovanna, Mirci-Danicar, Oana C., Mullanfiroze, Khushnuma, Pavasovic, Vesna, Rao, Anupama, Rao, Kanchan, Riley, Lynne, Samarasinghe, Sujith, Shenton, Geoff, Silva, Juliana, Vora, Ajay, Hough, Rachael, Amrolia, Persis J., and Ghorashian, Sara

Published
2024
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38. 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

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
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39. 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

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
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40. Impaired human hematopoiesis due to a cryptic intronic GATA1 splicing mutation

Author

Abdulhay, Nour J., Fiorini, Claudia, Verboon, Jeffrey M., Ludwig, Leif S., Ulirsch, Jacob C., Zieger, Barbara, Lareau, Caleb A., Mi, Xiaoli, Roy, Anindita, Obeng, Esther A., Erlacher, Miriam, Gupta, Namrata, Gabriel, Stacey B., Ebert, Benjamin L., Niemeyer, Charlotte M., Khoriaty, Rami N., Ancliff, Philip, Gazda, Hanna T., Wlodarski, Marcin W., and Sankaran, Vijay G.

Abstract

Studies of allelic variation underlying genetic blood disorders have provided important insights into human hematopoiesis. Most often, the identified pathogenic mutations result in loss-of-function or missense changes. However, assessing the pathogenicity of noncoding variants can be challenging. Here, we characterize two unrelated patients with a distinct presentation of dyserythropoietic anemia and other impairments in hematopoiesis associated with an intronic mutation in GATA1 that is 24 nucleotides upstream of the canonical splice acceptor site. Functional studies demonstrate that this single-nucleotide alteration leads to reduced canonical splicing and increased use of an alternative splice acceptor site that causes a partial intron retention event. The resultant altered GATA1 contains a five–amino acid insertion at the C-terminus of the C-terminal zinc finger and has no observable activity. Collectively, our results demonstrate how altered splicing of GATA1, which reduces levels of the normal form of this master transcription factor, can result in distinct changes in human hematopoiesis.

Published
2019
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41. A Single Centre Cohort Study of Monitoring B Cell Populations in the Bone Marrow and Peripheral Blood Post Tisagenlecleucel Therapy of Relapsed/Refractory Acute Lymphoblastic Leukaemia

Author

Fernandes, Sneha, Rauthan, Archana, Oporto Epuelas, Macarena, Berry, Katherine, Burridge, Saskia, Twigdon-Williams, Charlotte, Connor, Christopher, Davis, Mark, Gilmour, Kimberly, Thomas, Rebecca, Ancliff, Phil, Bartram, Jack, Chiesa, Robert, Lucchini, Giovanna, Pavasovic, Vesna, Rao, Anupama, Rao, Kanchan, Samarasinghe, Sujith, Silva, Juliana, Vora, Ajay, Amrolia, Persis, and Ghorashian, Sara

Abstract

Introduction:

Published
2023
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42. Outcomes for Children with High Risk Acute Myeloid Leukemia on the Myechild 01 International Phase III Clinical Trial

Author

Moore, Andrew, Maycock, Shanna, Leverger, Guy, Smith, Owen, Baruchel, Andre, Bertrand, Yves, Ancliff, Phil, Heaney, Nicholas, Shenton, Geoff, Petit, Arnaud, Bourquin, Jean-Pierre, Jackson, Aimee, Lawson, Anna, Amrolia, Persis, Michel, Gerard, Dalle, Jean-Hugues, Ansari, Marc, Lapillonne, Hélène, Dillon, Richard, Jovanovic, Jelena, Roumier, Christophe, Duployez, Nicolas, Harrison, Christine, Schwab, Claire, Cuccuini, Wendy, Lafage-Pochitaloff, Marina, Vyas, Paresh, Hirsch, Pierre, Veal, Gareth, Kearns, Pam, and Gibson, Brenda

Abstract

Background:Outcomes for pediatric acute myeloid leukemia (AML) remain disappointing, particularly for patients with poor risk cytogenetic/molecular genetic abnormalities and those who fail to achieve complete remission following course 1 of induction chemotherapy. Despite upfront allogeneic hematopoietic stem cell transplantation (HSCT) for these patients, high rates of relapse persist. The optimal approach to chemotherapy intensification and timing of HSCT for high risk (HR) patients remains unknown, with variable approaches employed by cooperative trial groups.

Published
2023
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43. Routine Whole Genome Sequencing for All Children with Hematological Malignancies Defines a New Standard of Care - Data of the First 152 Cases from the NHS England Genomic Medicine Service

Author

Hodder, Angus, Leiter, Sarah, Vedi, Aditi, May, Phillipa, Addy, Dilys, Ancliff, Phil, Cano-Flanagan, Julian, Chalker, Jane, Cheng, Danny, Clinch, Yasmin, Dryden, Caryl, Ghorashian, Sara, O'Connor, David, Pavasovic, Vesna, Rao, Anupama, Samarasinghe, Sujith, Stasevich, Iryna, Vora, Ajay, Hubank, Michael, Chitty, Dame Lyn, Behjati, Sam, and Bartram, Jack

Abstract

Background

Published
2023
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45. Targeting acute myeloid leukemia by drug-induced c-MYB degradation

Author

Walf-Vorderwülbecke, V, Pearce, K, Brooks, T, Hubank, M, van den Heuvel-Eibrink, M M, Zwaan, C M, Adams, S, Edwards, D, Bartram, J, Samarasinghe, S, Ancliff, P, Khwaja, A, Goulden, N, Williams, G, de Boer, J, and Williams, O

Abstract

Despite advances in our understanding of the molecular basis for particular subtypes of acute myeloid leukemia (AML), effective therapy remains a challenge for many individuals suffering from this disease. A significant proportion of both pediatric and adult AML patients cannot be cured and since the upper limits of chemotherapy intensification have been reached, there is an urgent need for novel therapeutic approaches. The transcription factor c-MYB has been shown to play a central role in the development and progression of AML driven by several different oncogenes, including mixed lineage leukemia (MLL)-fusion genes. Here, we have used a c-MYB gene expression signature from MLL-rearranged AML to probe the Connectivity Map database and identified mebendazole as a c-MYB targeting drug. Mebendazole induces c-MYB degradation via the proteasome by interfering with the heat shock protein 70 (HSP70) chaperone system. Transient exposure to mebendazole is sufficient to inhibit colony formation by AML cells, but not normal cord blood-derived cells. Furthermore, mebendazole is effective at impairing AML progression in vivo in mouse xenotransplantation experiments. In the context of widespread human use of mebendazole, our data indicate that mebendazole-induced c-MYB degradation represents a safe and novel therapeutic approach for AML.

Published
2018
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46. MECOM-associated syndrome: a heterogeneous inherited bone marrow failure syndrome with amegakaryocytic thrombocytopenia

Author

Germeshausen, Manuela, Ancliff, Phil, Estrada, Jaime, Metzler, Markus, Ponstingl, Eva, Rütschle, Horst, Schwabe, Dirk, Scott, Richard H., Unal, Sule, Wawer, Angela, Zeller, Bernward, and Ballmaier, Matthias

Abstract

Heterozygous mutations in MECOM (MDS1 and EVI1 complex locus) have been reported to be causative of a rare association of congenital amegakaryocytic thrombocytopenia and radioulnar synostosis. Here we report on 12 patients with congenital hypomegakaryocytic thrombocytopenia caused by MECOM mutations (including 10 novel mutations). The mutations affected different functional domains of the EVI1 protein. The spectrum of phenotypes was much broader than initially reported for the first 3 patients; we found familial as well as sporadic cases, and the clinical spectrum ranged from isolated radioulnar synostosis with no or mild hematological involvement to severe bone marrow failure without obvious skeletal abnormality. The clinical picture included radioulnar synostosis, bone marrow failure, clinodactyly, cardiac and renal malformations, B-cell deficiency, and presenile hearing loss. No single clinical manifestation was detected in all patients affected by MECOM mutations. Radioulnar synostosis and B-cell deficiency were observed only in patients with mutations affecting a short region in the C-terminal zinc finger domain of EVI1. We propose the term MECOM-associated syndrome for this heterogeneous hereditary disease and inclusion of MECOM sequencing in the diagnostic workup of congenital bone marrow failure.

Published
2018
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47. Lentiviral-mediated Gene Therapy for Patients with Fanconi Anemia [Group A]: Updated Results from Global RP-L102 Clinical Trials

Author

Czechowicz, Agnieszka, Sevilla, Julián, Booth, Claire, Agarwal, Rajni, Zubicaray, Josune, Río, Paula, Navarro, Susana, Chetty, Kritika, O'Toole, Grainne, Xu-Bayford, Jinhua, Ancliff, Philip, Sebastián, Elena, Choi, Grace, Zeini, Miriam, Nicoletti, Eileen, Wagner, John E, Rao, Gayatri R., Thrasher, Adrian J., Schwartz, Jonathan D., Roncarolo, Maria Grazia, and Bueren, Juan A.

Published
2022
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48. Acquisition of genome-wide copy number alterations in monozygotic twins with acute lymphoblastic leukemia

Author

Bateman, C, Colman, S, Chaplin, T, Young, B, Eden, T, Bhakta, M, Gratias, E, van Wering, E, Cazzaniga, G, Harrison, C, Hain, R, Ancliff, P, Ford, A, Kearney, L, Greaves, M, Bateman, Caroline M, Colman, Susan M, Chaplin, Tracy, Young, Bryan D, Eden, Tim O, Bhakta, Manoo, Gratias, Eric J, van Wering, Elisabeth R, Cazzaniga, Giovanni, Harrison, Christine J, Hain, Richard, Ancliff, Philip, Ford, Anthony M, Kearney, Lyndal, Greaves, Mel, Bateman, C, Colman, S, Chaplin, T, Young, B, Eden, T, Bhakta, M, Gratias, E, van Wering, E, Cazzaniga, G, Harrison, C, Hain, R, Ancliff, P, Ford, A, Kearney, L, Greaves, M, Bateman, Caroline M, Colman, Susan M, Chaplin, Tracy, Young, Bryan D, Eden, Tim O, Bhakta, Manoo, Gratias, Eric J, van Wering, Elisabeth R, Cazzaniga, Giovanni, Harrison, Christine J, Hain, Richard, Ancliff, Philip, Ford, Anthony M, Kearney, Lyndal, and Greaves, Mel

Abstract

Chimeric fusion genes are highly prevalent in childhood acute lymphoblastic leukemia (ALL) and are mostly prenatal, early genetic events in the evolutionary trajectory of this cancer. ETV6-RUNX1-positive ALL also has multiple ( approximately 6 per case) copy number alterations (CNAs) as revealed by genome-wide single-nucleotide polymorphism arrays. Recurrent CNAs are probably "driver" events contributing critically to clonal diversification and selection, but at diagnosis, their developmental timing is "buried" in the leukemia's covert natural history. This conundrum can be resolved with twin pairs. We identified and compared CNAs in 5 pairs of monozygotic twins with concordant ETV6-RUNX1-positive ALL and 1 pair discordant for ETV6-RUNX1 positive ALL. We compared, within each pair, CNAs classified as potential "driver" or "passenger" mutations based upon recurrency and, where known, gene function. An average of 5.1 (range 3-11) CNAs (excluding immunoglobulin/T-cell receptor alterations) were identified per case. All "driver" CNAs (total of 32) were distinct within each of the 5 twin pairs with concordant ALL. "Driver" CNAs in another twin with ALL were all absent in the shared ETV6-RUNX1-positive preleukemic clone of her healthy co-twin. These data place all "driver" CNAs secondary to the prenatal gene fusion event and most probably postnatal in the sequential, molecular pathogenesis of ALL.

Published
2010

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