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1. Leukaemia exposure alters the transcriptional profile and function of BCR::ABL1 negative macrophages in the bone marrow niche

Author

Dawson, Amy, Zarou, Martha M., Prasad, Bodhayan, Bittencourt-Silvestre, Joana, Zerbst, Désirée, Himonas, Ekaterini, Hsieh, Ya-Ching, van Loon, Isabel, Blanco, Giovanny Rodriguez, Ianniciello, Angela, Kerekes, Zsombor, Krishnan, Vaidehi, Agarwal, Puneet, Almasoudi, Hassan, McCluskey, Laura, Hopcroft, Lisa E. M., Scott, Mary T., Baquero, Pablo, Dunn, Karen, Vetrie, David, Copland, Mhairi, Bhatia, Ravi, Coffelt, Seth B., Tiong, Ong Sin, Wheadon, Helen, Zanivan, Sara, Kirschner, Kristina, and Helgason, G. Vignir

Published
2024
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6. From Genomes to Vaccines: Leishmania as a Model

Author

Almeida, Renata, Norrish, Alan, Levick, Mark, Vetrie, David, Freeman, Tom, Vilo, Jaak, Ivens, Alasdair, Lange, Uta, Stober, Carmel, McCann, Sharon, and Blackwell, Jenefer M.

Published
2002

9. Supplementary Table S3 from Epigenetic Reprogramming Sensitizes CML Stem Cells to Combined EZH2 and Tyrosine Kinase Inhibition

Author

Scott, Mary T., primary, Korfi, Koorosh, primary, Saffrey, Peter, primary, Hopcroft, Lisa E.M., primary, Kinstrie, Ross, primary, Pellicano, Francesca, primary, Guenther, Carla, primary, Gallipoli, Paolo, primary, Cruz, Michelle, primary, Dunn, Karen, primary, Jorgensen, Heather G., primary, Cassels, Jennifer E., primary, Hamilton, Ashley, primary, Crossan, Andrew, primary, Sinclair, Amy, primary, Holyoake, Tessa L., primary, and Vetrie, David, primary

Published
2023
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10. Supplementary Figures S1 - S17 from Epigenetic Reprogramming Sensitizes CML Stem Cells to Combined EZH2 and Tyrosine Kinase Inhibition

Author

Scott, Mary T., primary, Korfi, Koorosh, primary, Saffrey, Peter, primary, Hopcroft, Lisa E.M., primary, Kinstrie, Ross, primary, Pellicano, Francesca, primary, Guenther, Carla, primary, Gallipoli, Paolo, primary, Cruz, Michelle, primary, Dunn, Karen, primary, Jorgensen, Heather G., primary, Cassels, Jennifer E., primary, Hamilton, Ashley, primary, Crossan, Andrew, primary, Sinclair, Amy, primary, Holyoake, Tessa L., primary, and Vetrie, David, primary

Published
2023
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11. Data from Epigenetic Reprogramming Sensitizes CML Stem Cells to Combined EZH2 and Tyrosine Kinase Inhibition

Author

Scott, Mary T., primary, Korfi, Koorosh, primary, Saffrey, Peter, primary, Hopcroft, Lisa E.M., primary, Kinstrie, Ross, primary, Pellicano, Francesca, primary, Guenther, Carla, primary, Gallipoli, Paolo, primary, Cruz, Michelle, primary, Dunn, Karen, primary, Jorgensen, Heather G., primary, Cassels, Jennifer E., primary, Hamilton, Ashley, primary, Crossan, Andrew, primary, Sinclair, Amy, primary, Holyoake, Tessa L., primary, and Vetrie, David, primary

Published
2023
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12. Dual targeting of p53 and c-MYC selectively eliminates leukaemic stem cells

Author

Abraham, Sheela A., Hopcroft, Lisa E.M., Carrick, Emma, Drotar, Mark E., Dunn, Karen, Williamson, Andrew J.K., Korfi, Koorosh, Baquero, Pablo, Park, Laura E., Scott, Mary T., Pellicano, Francesca, Pierce, Andrew, Copland, Mhairi, Nourse, Craig, Grimmond, Sean M., Vetrie, David, Whetton, Anthony D., and Holyoake, Tessa L.

Subjects
Development and progression, Genetic aspects, Properties, Methods, Health aspects, Tumor proteins -- Properties, Cancer cells -- Health aspects -- Genetic aspects, Molecular targeted therapy -- Methods, Stem cells -- Genetic aspects -- Health aspects, Chronic myeloid leukemia -- Genetic aspects -- Development and progression
Abstract

BCR-ABL1 is a chimaeric oncogene arising from the t(9;22)(q34;q11) chromosomal translocation. The resultant protein tyrosine kinase (PTK) drives signalling events (1) and transforms HSCs. BCR-ABL activity in HSCs causes CML, [...], Chronic myeloid leukaemia (CML) arises after transformation of a haemopoietic stem cell (HSC) by the protein-tyrosine kinase BCR-ABL. Direct inhibition of BCR-ABL kinase has revolutionized disease management, but fails to eradicate leukaemic stem cells (LSCs), which maintain CML. LSCs are independent of BCR-ABL for survival, providing a rationale for identifying and targeting kinase-independent pathways. Here we show-using proteomics, transcriptomics and network analyses-that in human LSCs, aberrantly expressed proteins, in both imatinib-responder and non-responder patients, are modulated in concert with p53 (also known as TP53) and c-MYC regulation. Perturbation of both p53 and c-MYC, and not BCR-ABL itself, leads to synergistic cell kill, differentiation, and near elimination of transplantable human LSCs in mice, while sparing normal HSCs. This unbiased systems approach targeting connected nodes exemplifies a novel precision medicine strategy providing evidence that LSCs can be eradicated.

Published
2016
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14. The Spliceosome: A New Therapeutic Target in Chronic Myeloid Leukaemia

Author

Lebecque, Benjamin, primary, Bourgne, Celine, additional, Munje, Chinmay, additional, Berger, Juliette, additional, Tassin, Thomas, additional, Cony-Makhoul, Pascale, additional, Guerci-Bresler, Agnès, additional, Johnson-Ansah, Hyacinthe, additional, Liu, Wei, additional, Saugues, Sandrine, additional, Tchirkov, Andrei, additional, Vetrie, David, additional, Copland, Mhairi, additional, and Berger, Marc G., additional

Published
2022
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16. Requirement of bic/microRNA-155 for Normal Immune Function

Author

Rodriguez, Antony, Vigorito, Elena, Clare, Simon, Warren, Madhuri V., Couttet, Philippe, Soond, Dalya R., van Dongen, Stijn, Grocock, Russell J., Das, Partha P., Miska, Eric A., Vetrie, David, Okkenhaug, Klaus, Enright, Anton J., Dougan, Gordon, Turner, Martin, and Bradley, Allan

Published
2007
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19. Uncoupling p53 from an Embryonic Regulome Exhausts Quiescent CML Stem Cells through Inhibition of a HIF1alpha Molecular Program

Author

Scott, Mary T, primary, Liu, Wei, additional, Mitchell, Rebecca, additional, Clarke, Cassie, additional, Almasoudi, Hassan, additional, Warren, Felix, additional, Kinstrie, Ross, additional, Dunn, Karen, additional, Pritchard, John, additional, Drotar, Mark E, additional, Michie, Alison M, additional, Jørgensen, Heather G, additional, Higgins, Brian, additional, Copland, Mhairi, additional, and Vetrie, David, additional

Published
2021
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20. ULK1 inhibition promotes oxidative stress–induced differentiation and sensitizes leukemic stem cells to targeted therapy

Author

Ianniciello, Angela, primary, Zarou, Martha M., additional, Rattigan, Kevin M., additional, Scott, Mary, additional, Dawson, Amy, additional, Dunn, Karen, additional, Brabcova, Zuzana, additional, Kalkman, Eric R., additional, Nixon, Colin, additional, Michie, Alison M., additional, Copland, Mhairi, additional, Vetrie, David, additional, Ambler, Martin, additional, Saxty, Barbara, additional, and Helgason, G. Vignir, additional

Published
2021
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21. Autosomal-dominant microtia linked to five tandem copies of a copy-number-variable region at chromosome 4p16

Author

Balikova, Irina, Martens, Kevin, Melotte, Cindy, Amyere, Mustapha, Vooren, Steven Van, Moreau, Yves, Vetrie, David, Fiegler, Heike, Carter, Nigel P., Liehr, Thomas, Vikkula, Miikka, Matthijs, Gert, Fryns, Jean-Pierre, Casteels, Ingele, Devriendt, Koen, and Vermeesch, Joris Robert

Subjects
Genetic disorders -- Research, Coloboma -- Genetic aspects, Coloboma -- Causes of, Biological sciences
Abstract

A family with a novel autosomal-dominantly inherited syndrome characterized by microtia, eye coloboma, and imperforation of the nasolacrimal duct is presented. It is concluded that it is the first Mendelian inherited genetic disorder associated with the amplification of a copy-number variation (CNV).

Published
2008

23. Identification and analysis of functional elements in 1% of the human genome by the ENCODE pilot project

Author

Birney, Ewan, Stamatoyannopoulos, John A., Dutta, Anindya, Guigo, Roderic, Gingeras, Thomas R., Margulies, Elliott H., Weng, Zhiping, Snyder, Michael, Dermitzakis, Emmanouil T., Thurman, Robert E., Kuehn, Michael S., Taylor, Christopher M., Neph, Shane, Koch, Christoph M., Asthana, Saurabh, Malhotra, Ankit, Adzhubei, Ivan, Greenbaum, Jason A., Andrews, Robert M., Flicek, Paul, Boyle, Patrick J., Cao, Hua, Carter, Nigel P., Clelland, Gayle K., Davis, Sean, Day, Nathan, Dhami, Pawandeep, Dillon, Shane C., Dorschner, Michael O., Fiegler, Heike, Giresi, Paul G., Goldy, Jeff, Hawrylycz, Michael, Haydock, Andrew, Humbert, Richard, James, Keith D., Johnson, Brett E., Johnson, Ericka M., Frum, Tristan T., Rosenzweig, Elizabeth R., Karnani, Neerja, Lee, Kirsten, Lefebvre, Gregory C., Navas, Patrick A., Neri, Fidencio, Parker, Stephen C. J., Sabo, Peter J., Sandstrom, Richard, Shafer, Anthony, Vetrie, David, Weaver, Molly, Wilcox, Sarah, Yu1, Man, Collins, Francis S., Dekker, Job, Lieb, Jason D., Tullius, Thomas D., Crawford, Gregory E., Sunyaev, Shamil, Noble, William S., Dunham, Ian, Denoeud, France, Reymond, Alexandre, Kapranov, Philipp, Rozowsky, Joel, Zheng, Deyou, Castelo, Robert, Frankish, Adam, Harrow, Jennifer, Ghosh, Srinka, Sandelin, Albin, Hofacker, Ivo L., Baertsch, Robert, Keefe, Damian, Dike, Sujit, Cheng, Jill, Hirsch, Heather A., Sekinger, Edward A., Lagarde, Julien, Abril, Josep F., Shahab, Atif, Flamm, Christoph, Fried, Claudia, Hackermuller, Jorg, Hertel, Jana, Lindemeyer, Manja, Missal, Kristin, Tanzer, Andrea, Washietl, Stefan, Korbel, Jan, Emanuelsson, Olof, Pedersen, Jakob S., Holroyd, Nancy, Taylor, Ruth, Swarbreck, David, Matthews, Nicholas, Dickson, Mark C., Thomas, Daryl J., Weirauch, Matthew T., Gilbert, James, Drenkow, Jorg, Bell, Ian, Zhao, XiaoDong, Srinivasan, K.G., Sung, Wing-Kin, Ooi, Hong Sain, Chiu, Kuo Ping, Foissac, Sylvain, Alioto, Tyler, Brent, Michael, Pachter, Lior, Tress, Michael L., Valencia, Alfonso, Choo, Siew Woh, Choo, Chiou Yu, Ucla, Catherine, Manzano, Caroline, Wyss, Carine, Cheung, Evelyn, Clark, Taane G., Brown, James B., Ganesh, Madhavan, Patel, Sandeep, Tammana, Hari, Chrast, Jacqueline, Henrichsen, Charlotte N., Kai, Chikatoshi, Kawai, Jun, Nagalakshmi, Ugrappa, Wu, Jiaqian, Lian, Zheng, Lian, Jin, Newburger, Peter, Zhang, Xueqing, Bickel, Peter, Mattick, John S., Carninci, Piero, Hayashizaki, Yoshihide, Weissman, Sherman, Hubbard, Tim, Myers, Richard M., Rogers, Jane, Stadler, Peter F., Lowe, Todd M., Wei, Chia-Lin, Ruan, Yijun, Struhl, Kevin, Gerstein, Mark, Antonarakis, Stylianos E., Fu, Yutao, Green, Eric D., Karaoz, Ulaş, Siepel, Adam, Taylor, James, Liefer, Laura A., Wetterstrand, Kris A., Good, Peter J., Feingold, Elise A., Guyer, Mark S., Cooper, Gregory M., Asimenos, George, Dewey, Colin N., Hou, Minmei, Nikolaev, Sergey, Montoya-Burgos, Juan I., Loytynoja, Ari, Whelan, Simon, Pardi, Fabio, Massingham, Tim, Huang, Haiyan, Zhang, Nancy R., Holmes, Ian, Mullikin, James C., Ureta-Vidal, Abel, Paten, Benedict, Seringhaus, Michael, Church, Deanna, Rosenbloom, Kate, Kent, W. James, Stone, Eric A., Batzoglou, Serafim, Goldman, Nick, Hardison, Ross C., Haussler, David, Miller, Webb, Sidow, Arend, Trinklein, Nathan D., Zhang, Zhengdong D., Barrera, Leah, Stuart, Rhona, King, David C., Ameur, Adam, Enroth, Stefan, Bieda, Mark C., Kim, Jonghwan, Bhinge, Akshay A., Jiang, Nan, Liu, Jun, Yao, Fei, Vega, Vinsensius B., Lee, Charlie W.H., Ng, Patrick, Yang, Annie, Moqtaderi, Zarmik, Zhu, Zhou, Xu, Xiaoqin, Squazzo, Sharon, Oberley, Matthew J., Inman, David, Singer, Michael A., Richmond, Todd A., Munn, Kyle J., Rada-Iglesias, Alvaro, Wallerman, Ola, Komorowski, Jan, Fowler, Joanna C., Couttet, Phillippe, Bruce, Alexander W., Dovey, Oliver M., Ellis, Peter D., Langford, Cordelia F., Nix, David A., Euskirchen, Ghia, Hartman, Stephen, Urban, Alexander E., Kraus, Peter, Van Calcar, Sara, Heintzman, Nate, Hoon Kim, Tae, Wang, Kun, Qu, Chunxu, Hon, Gary, Luna, Rosa, Glass, Christopher K., Rosenfeld, M. Geoff, Aldred, Shelley Force, Cooper, Sara J., Halees, Anason, Lin, Jane M., Shulha, Hennady P., Zhang, Xiaoling, Xu, Mousheng, Haidar, Jaafar N. S., Yu, Yong, Birney*, Ewan, Iyer, Vishwanath R., Green, Roland D., Wadelius, Claes, Farnham, Peggy J., Ren, Bing, Harte, Rachel A., Hinrichs, Angie S., Trumbower, Heather, Clawson, Hiram, Hillman-Jackson, Jennifer, Zweig, Ann S., Smith, Kayla, Thakkapallayil, Archana, Barber, Galt, Kuhn, Robert M., Karolchik, Donna, Armengol, Lluis, Bird, Christine P., de Bakker, Paul I. W., Kern, Andrew D., Lopez-Bigas, Nuria, Martin, Joel D., Stranger, Barbara E., Woodroffe, Abigail, Davydov, Eugene, Dimas, Antigone, Eyras, Eduardo, Hallgrimsdottir, Ingileif B., Huppert, Julian, Zody, Michael C., Abecasis, Goncalo R., Estivill, Xavier, Bouffard, Gerard G., Guan, Xiaobin, Hansen, Nancy F., Idol, Jacquelyn R., Maduro, Valerie V.B., Maskeri, Baishali, McDowell, Jennifer C., Park, Morgan, Thomas, Pamela J., Young, Alice C., Blakesley, Robert W., Baylor College of Medicine, Human Genome Sequencing Center, Muzny, Donna M., Sodergren, Erica, Wheeler, David A., Worley, Kim C., Jiang, Huaiyang, Weinstock, George M., Gibbs, Richard A., Graves, Tina, Fulton, Robert, Mardis, Elaine R., Wilson, Richard K., Clamp, Michele, Cuff, James, Gnerre, Sante, Jaffe, David B., Chang, Jean L., Lindblad-Toh, Kerstin, Lander, Eric S., Koriabine, Maxim, Nefedov, Mikhail, Osoegawa, Kazutoyo, Yoshinaga, Yuko, Zhu, Baoli, and de Jong, Pieter J.

Subjects
Environmental issues, Science and technology, Zoology and wildlife conservation
Abstract

Author(s): The ENCODE Project Consortium; Analysis Coordination; Ewan Birney (corresponding author) [1]; John A. Stamatoyannopoulos (corresponding author) [2]; Anindya Dutta (corresponding author) [3]; Roderic Guigó (corresponding author) [4, 5]; Thomas [...]

Published
2007
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25. A KDM4A-PAF1-mediated epigenomic network is essential for acute myeloid leukemia cell self-renewal and survival

Author

Massett, Matthew E, primary, Monaghan, Laura, additional, Patterson, Shaun, additional, Mannion, Niamh, additional, Bunschoten, Roderick P, additional, Hoose, Alex, additional, Marmiroli, Sandra, additional, Liskamp, Robert MJ, additional, Jørgensen, Heather G, additional, Vetrie, David, additional, Michie, Alison M, additional, and Huang, Xu, additional

Published
2020
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26. The leukaemia stem cell: similarities, differences and clinical prospects in CML and AML

Author

Vetrie, David, Helgason, Vignir, and Copland, Mhairi

Subjects
Myeloid, General Mathematics, Context (language use), History, 21st Century, 03 medical and health sciences, Myelogenous, 0302 clinical medicine, Drug Development, Cancer stem cell, hemic and lymphatic diseases, Leukemia, Myelogenous, Chronic, BCR-ABL Positive, Biomarkers, Tumor, Medicine, Animals, Humans, Molecular Targeted Therapy, Progenitor cell, neoplasms, business.industry, Applied Mathematics, Research, Disease Management, History, 20th Century, medicine.disease, Haematopoiesis, Leukemia, Leukemia, Myeloid, Acute, medicine.anatomical_structure, Cell Transformation, Neoplastic, 030220 oncology & carcinogenesis, Cancer research, Neoplastic Stem Cells, Disease Susceptibility, Stem cell, business
Abstract

For two decades, leukaemia stem cells (LSCs) in chronic myeloid leukaemia (CML) and acute myeloid leukaemia (AML) have been advanced paradigms for the cancer stem cell field. In CML, the acquisition of the fusion tyrosine kinase BCR–ABL1 in a haematopoietic stem cell drives its transformation to become a LSC. In AML, LSCs can arise from multiple cell types through the activity of a number of oncogenic drivers and pre-leukaemic events, adding further layers of context and genetic and cellular heterogeneity to AML LSCs not observed in most cases of CML. Furthermore, LSCs from both AML and CML can be refractory to standard-of-care therapies and persist in patients, diversify clonally and serve as reservoirs to drive relapse, recurrence or progression to more aggressive forms. Despite these complexities, LSCs in both diseases share biological features, making them distinct from other CML or AML progenitor cells and from normal haematopoietic stem cells. These features may represent Achilles’ heels against which novel therapies can be developed. Here, we review many of the similarities and differences that exist between LSCs in CML and AML and examine the therapeutic strategies that could be used to eradicate them.

Published
2019

27. Pelizaeus-Merzbacher disease: identification of Xq22 proteolipid-protein duplications and characterization of breakpoints by interphase FISH

Author

Woodward, Karen, Kendall, Elaine, Vetrie, David, and Malcolm, Sue

Subjects
Genetic disorders -- Research, Chromosome mapping -- Usage, Demyelination -- Genetic aspects, Biological sciences
Abstract

Duplications of the proteolipid protein (PLP) gene have been found in a fraction of patients, suggesting that, in addition to coding-region or splice-site mutations, overdosage of the gene can cause Pelizaeus-Merzbacher disease (PMD). Duplications are a major cause of PMD and for that reason it has been suggested that interphase fluorescence in situ hybridization (FISH) would be a good method for diagnosis and identification of female carriers. The extent of the duplication was analyzed in five paients with four asymptomatic carrier mothers. PMD is an X-linked dysmyelinating central nervous system (CNS) disorder, and Xq22 proteolipid-protein duplications have been identified.

Published
1998

29. Identification of Genetic Aberrations on Chromosome 22 Outside the NF2 Locus in Schwannomatosis and Neurofibromatosis Type 2

Author

Buckley, Patrick G., Mantripragada, Kiran K., de Ståhl, Teresita Díaz, Piotrowski, Arkadiusz, Hansson, Caisa M., Kiss, Hajnalka, Vetrie, David, Ernberg, Ingemar T., Nordenskjöld, Magnus, Bolund, Lars, Sainio, Markku, Rouleau, Guy A., Niimura, Michihito, Wallace, Andrew J., Evans, Gareth D. R., Grigelionis, Gintautas, Menzel, Uwe, and Dumanski, Jan P.

Published
2005
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30. Binding sites for metabolic disease related transcription factors inferred at base pair resolution by chromatin immunoprecipitation and genomic microarrays

Author

Rada-Iglesias, Alvaro, Wallerman, Ola, Koch, Christoph, Ameur, Adam, Enroth, Stefan, Clelland, Gayle, Wester, Kenneth, Wilcox, Sarah, Dovey, Oliver M., Ellis, Peter D., Wraight, Vicki L., James, Keith, Andrews, Rob, Langford, Cordelia, Dhami, Pawandeep, Carter, Nigel, Vetrie, David, Pontén, Fredrik, Komorowski, Jan, Dunham, Ian, and Wadelius, Claes

Published
2005

34. The gene involved in X-linked agammaglobulinaemia is a member of the src family of protein-tyrosine kinases

Author

Vetrie, David, Vorechovsky, Igor, Sideras, Paschalis, Holland, Jill, Davies, Angela, Flinter, Frances, Hammarstrom, Lennart, Kinnon, Christine, Levinsky, Roland, Bobrow, Martin, Smith, C.I. Edvard, and Bentley, David R.

Subjects
Agammaglobulinemia -- Genetic aspects, B cells -- Abnormalities, Proto-oncogenes -- Research, Protein tyrosine kinase -- Genetic aspects, Environmental issues, Science and technology, Zoology and wildlife conservation
Abstract

A gene belonging to the src group of proto-oncogenes has been associated with X-linked agammaglobulinemia (XLA), a hereditary immunodeficiency disease occurring in males. The gene, which was isolated in yeast artificial chromosome using complementary DNA and which has been designated atk, probably produces the defective development of B cells in the bone marrow that causes XLA. Furthermore, atk also carries the genetic information for a protein-tyrosine kinase.

Published
1993

38. Epigenetic Reprogramming Sensitizes CML Stem Cells to Combined EZH2 and Tyrosine Kinase Inhibition

Author

Scott, Mary T., Korfi, Koorosh, Saffrey, Peter, Hopcroft, Lisa E.M., Kinstrie, Ross, Pellicano, Francesca, Guenther, Carla, Gallipoli, Paolo, Cruz, Michelle, Dunn, Karen, Jorgensen, Heather G., Cassels, Jennifer E., Hamilon, Ashley, Crossan, Andrew, Sinclair, Amy, Holyoake, Tessa L., Vetrie, David, Gallipoli, Paolo [0000-0001-7254-2253], and Apollo - University of Cambridge Repository

Subjects
Fusion Proteins, bcr-abl, Apoptosis, macromolecular substances, Cellular Reprogramming, Hematopoietic Stem Cells, Article, respiratory tract diseases, Epigenesis, Genetic, Mice, Drug Resistance, Neoplasm, hemic and lymphatic diseases, Cell Line, Tumor, Leukemia, Myelogenous, Chronic, BCR-ABL Positive, Neoplastic Stem Cells, Animals, Humans, Enhancer of Zeste Homolog 2 Protein, Protein Kinase Inhibitors
Abstract

UNLABELLED: A major obstacle to curing chronic myeloid leukemia (CML) is residual disease maintained by tyrosine kinase inhibitor (TKI)-persistent leukemic stem cells (LSC). These are BCR-ABL1 kinase independent, refractory to apoptosis, and serve as a reservoir to drive relapse or TKI resistance. We demonstrate that Polycomb Repressive Complex 2 is misregulated in chronic phase CML LSCs. This is associated with extensive reprogramming of H3K27me3 targets in LSCs, thus sensitizing them to apoptosis upon treatment with an EZH2-specific inhibitor (EZH2i). EZH2i does not impair normal hematopoietic stem cell survival. Strikingly, treatment of primary CML cells with either EZH2i or TKI alone caused significant upregulation of H3K27me3 targets, and combined treatment further potentiated these effects and resulted in significant loss of LSCs compared to TKI alone, in vitro, and in long-term bone marrow murine xenografts. Our findings point to a promising epigenetic-based therapeutic strategy to more effectively target LSCs in patients with CML receiving TKIs. SIGNIFICANCE: In CML, TKI-persistent LSCs remain an obstacle to cure, and approaches to eradicate them remain a significant unmet clinical need. We demonstrate that EZH2 and H3K27me3 reprogramming is important for LSC survival, but renders LSCs sensitive to the combined effects of EZH2i and TKI. This represents a novel approach to more effectively target LSCs in patients receiving TKI treatment. Cancer Discov; 6(11); 1248-57. ©2016 AACR.See related article by Xie et al., p. 1237This article is highlighted in the In This Issue feature, p. 1197.

Published
2017
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39. Whole-genome microarrays of fission yeast: characteristics, accuracy, reproducibility, and processing of array data

Author

Chen Dongrong, Rustici Gabriella, Penkett Chris J, Mata Juan, Burns Gavin, Lyne Rachel, Langford Cordelia, Vetrie David, and Bähler Jürg

Subjects
Biotechnology, TP248.13-248.65, Genetics, QH426-470
Abstract

Abstract Background The genome of the fission yeast Schizosaccharomyces pombe has recently been sequenced, setting the stage for the post-genomic era of this increasingly popular model organism. We have built fission yeast microarrays, optimised protocols to improve array performance, and carried out experiments to assess various characteristics of microarrays. Results We designed PCR primers to amplify specific probes (180–500 bp) for all known and predicted fission yeast genes, which are printed in duplicate onto separate regions of glass slides together with control elements (~13,000 spots/slide). Fluorescence signal intensities depended on the size and intragenic position of the array elements, whereas the signal ratios were largely independent of element properties. Only the coding strand is covalently linked to the slides, and our array elements can discriminate transcriptional direction. The microarrays can distinguish sequences with up to 70% identity, above which cross-hybridisation contributes to the signal intensity. We tested the accuracy of signal ratios and measured the reproducibility of array data caused by biological and technical factors. Because the technical variability is lower, it is best to use samples prepared from independent biological experiments to obtain repeated measurements with swapping of fluorochromes to prevent dye bias. We also developed a script that discards unreliable data and performs a normalization to correct spatial artefacts. Conclusions This paper provides data for several microarray properties that are rarely measured. The results define critical parameters for microarray design and experiments and provide a framework to optimise and interpret array data. Our arrays give reproducible and accurate expression ratios with high sensitivity. The scripts for primer design and initial data processing as well as primer sequences and detailed protocols are available from our website.

Published
2003
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43. Repositioned to kill stem cells

Author

Holyoake, Tessa and Vetrie, David

Subjects
Analysis, Research, Chemotherapy -- Analysis, Cancer research -- Analysis, Drug resistance -- Analysis, Stem cells -- Research, Chronic myeloid leukemia -- Research, Enzyme inhibitors -- Research, Oncology, Experimental, Cancer -- Chemotherapy -- Research
Abstract

Chemotherapy-resistant cancer stem cells make it hard to cure many forms of the disease. Repositioning an existing drug to tackle this problem could significantly improve treatment for one form of [...]

Published
2015

44. Dual targeting of P53 and C-MYC induces selective elimination of leukemic stem cells

Author

Abraham, Sheela A., Hopcroft, Lisa E.M., Carrick, Emma, Drotar, Mark E., Dunn, Karen, Williamson, Andrew J.K., Korfi, Koorosh, Baquero, Pablo, Park, Laura E., Scott, Mary T., Pellicano, Francesca, Pierce, Andrew, Copland, Mhairi, Nourse, Craig, Grimmond, Sean M., Vetrie, David, Whetton, Anthony D., and Holyoake, Tessa L.

Subjects
hemic and lymphatic diseases, neoplasms
Abstract

Chronic myeloid leukaemia (CML) arises after transformation of a haemopoietic stem cell (HSC) by the protein-tyrosine kinase BCR–ABL. Direct inhibition of BCR–ABL kinase has revolutionized disease management, but fails to eradicate leukaemic stem cells (LSCs), which maintain CML. LSCs are independent of BCR–ABL for survival, providing a rationale for identifying and targeting kinase-independent pathways. Here we show—using proteomics, transcriptomics and network analyses—that in human LSCs, aberrantly expressed proteins, in both imatinib-responder and non-responder patients, are modulated in concert with p53 (also known as TP53) and c-MYC regulation. Perturbation of both p53 and c-MYC, and not BCR–ABL itself, leads to synergistic cell kill, differentiation, and near elimination of transplantable human LSCs in mice, while sparing normal HSCs. This unbiased systems approach targeting connected nodes exemplifies a novel precision medicine strategy providing evidence that LSCs can be eradicated.

Published
2016

45. Functional diversity for REST (NRSF) is defined by in vivo binding affinity hierarchies at the DNA sequence level

Author

Bruce, Alexander W., Lopez-Contreras, Andres J., Flicek, Paul, Down, Thomas A., Dhami, Pawandeep, Dillon, Shane C., Koch, Christoph M., Langford, Cordelia F., Dunham, Ian, Andrews, Robert M., and Vetrie, David

Subjects
Nucleotide sequence -- Analysis, Biological diversity -- Research, DNA binding proteins -- Research, Mammals -- Genetic aspects, Genetic transcription -- Research, Health
Published
2009

46. The landscape of histone modifications across 1% of the human genome in five human cell lines

Author

Koch, Christoph M., Clelland, Gayle K., James, Keith D., Dhami, Pawandeep, Vetrie, David, Andrews, Robert M., Lefebvre, Gregory C., Langford, Cordelia F., Dunham, Ian, Wilcox, Sarah, Flicek, Paul, Beare, David, Bruce, Alexander W., Zhiping Weng, Dillon, Shane C., Fowler, Joanna C., Dovey, oliver M., Birney, Ewan, Karaoz, Ulas, Couttet, Phillippe, Ellis, Peter D., and Carter, Nigel P.

Subjects
Histones -- Analysis, Cell lines -- Analysis, Genetic transcription -- Analysis, Health
Abstract

The study of modified maps of histone in five human cell lines reveals the differences in transcription of the different cell lines.

Published
2007

48. Epigenetic Reprogramming Sensitizes CML Stem Cells to Combined EZH2 and Tyrosine Kinase Inhibition

Author

Scott, Mary T., primary, Korfi, Koorosh, additional, Saffrey, Peter, additional, Hopcroft, Lisa E.M., additional, Kinstrie, Ross, additional, Pellicano, Francesca, additional, Guenther, Carla, additional, Gallipoli, Paolo, additional, Cruz, Michelle, additional, Dunn, Karen, additional, Jorgensen, Heather G., additional, Cassels, Jennifer E., additional, Hamilton, Ashley, additional, Crossan, Andrew, additional, Sinclair, Amy, additional, Holyoake, Tessa L., additional, and Vetrie, David, additional

Published
2016
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49. Identifying gene regulatory elements by genomic microarray mapping of DNasel hypersensitive sites

Author

Follows, George A., Scott, Mike A., Dunham, Ian, Dhami, Pawan, Donaldson, Ian J., Janes, Mary E., Gottgens, Berthold, Koch, Christoph, Vetrie, David, Bruce, Alexander W., Smith, Aileen M., Green, Anthony R., Campbell, Peter J., and Dillon, Shane C.

Subjects
DNA microarrays -- Usage, Gene expression -- Analysis, Hybridization -- Analysis, Human genome -- Research, Health
Abstract

The development of a novel genomic array-based approach to DNasel hypersensitive site mapping (ADHM) that permits precise, large-scale identification of such sites from as few as five million cells is reported. ADHM provides a powerful approach to identifying DNasel hypersensitive sites across large genomic regions.

Published
2006

50. From genomes to vaccines: Leishmania as a model:Leishmania as a model

Author

Almeida, Renata, Norrish, Alan, Levick, Mark, Vetrie, David, Freeman, Tom, Vilo, Jaak, Ivens, Alasdair, Lange, Uta, Stober, Carmel, McCann, Sharon, and Blackwell, Jenefer M

Subjects
Leishmania, Protozoan Vaccines, Proteome, Gene Expression Profiling, Genes, Protozoan, Protozoan Proteins, Vaccines, DNA, Animals, Humans, Genome, Protozoan, Oligonucleotide Array Sequence Analysis
Abstract

The 35 Mb genome of Leishmania should be sequenced by late 2002. It contains approximately 8500 genes that will probably translate into more than 10 000 proteins. In the laboratory we have been piloting strategies to try to harness the power of the genome-proteome for rapid screening of new vaccine candidate. To this end, microarray analysis of 1094 unique genes identified using an EST analysis of 2091 cDNA clones from spliced leader libraries prepared from different developmental stages of Leishmania has been employed. The plan was to identify amastigote-expressed genes that could be used in high-throughput DNA-vaccine screens to identify potential new vaccine candidates. Despite the lack of transcriptional regulation that polycistronic transcription in Leishmania dictates, the data provide evidence for a high level of post-transcriptional regulation of RNA abundance during the developmental cycle of promastigotes in culture and in lesion-derived amastigotes of Leishmania major. This has provided 147 candidates from the 1094 unique genes that are specifically upregulated in amastigotes and are being used in vaccine studies. Using DNA vaccination, it was demonstrated that pooling strategies can work to identify protective vaccines, but it was found that some potentially protective antigens are masked by other disease-exacerbatory antigens in the pool. A total of 100 new vaccine candidates are currently being tested separately and in pools to extend this analysis, and to facilitate retrospective bioinformatic analysis to develop predictive algorithms for sequences that constitute potentially protective antigens. We are also working with other members of the Leishmania Genome Network to determine whether RNA expression determined by microarray analyses parallels expression at the protein level. We believe we are making good progress in developing strategies that will allow rapid translation of the sequence of Leishmania into potential interventions for disease control in humans.

Published
2002
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