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217 results on '"De Braekeleer, Etienne"'

1. METTL1-mediated m7G modification of Arg-TCT tRNA drives oncogenic transformation

Author

Orellana, Esteban A., Liu, Qi, Yankova, Eliza, Pirouz, Mehdi, De Braekeleer, Etienne, Zhang, Wencai, Lim, Jihoon, Aspris, Demetrios, Sendinc, Erdem, Garyfallos, Dimitrios A., Gu, Muxin, Ali, Raja, Gutierrez, Alejandro, Mikutis, Sigitas, Bernardes, Gonçalo J.L., Fischer, Eric S., Bradley, Allan, Vassiliou, George S., Slack, Frank J., Tzelepis, Konstantinos, and Gregory, Richard I.

Published
2021
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3. Small-molecule inhibition of METTL3 as a strategy against myeloid leukaemia

Author

Yankova, Eliza, Blackaby, Wesley, Albertella, Mark, Rak, Justyna, De Braekeleer, Etienne, Tsagkogeorga, Georgia, Pilka, Ewa S., Aspris, Demetrios, Leggate, Dan, Hendrick, Alan G., Webster, Natalie A., Andrews, Byron, Fosbeary, Richard, Guest, Patrick, Irigoyen, Nerea, and Eleftheriou, Maria

Subjects
Enzyme inhibitors -- Usage -- Health aspects, Methyltransferases -- Physiological aspects, Myelocytic leukemia -- Care and treatment, Nonlymphoid leukemia -- Care and treatment, Environmental issues, Science and technology, Zoology and wildlife conservation
Abstract

N.sup.6-methyladenosine (m.sup.6A) is an abundant internal RNA modification.sup.1,2 that is catalysed predominantly by the METTL3-METTL14 methyltransferase complex.sup.3,4. The m.sup.6A methyltransferase METTL3 has been linked to the initiation and maintenance of acute myeloid leukaemia (AML), but the potential of therapeutic applications targeting this enzyme remains unknown.sup.5-7. Here we present the identification and characterization of STM2457, a highly potent and selective first-in-class catalytic inhibitor of METTL3, and a crystal structure of STM2457 in complex with METTL3-METTL14. Treatment of tumours with STM2457 leads to reduced AML growth and an increase in differentiation and apoptosis. These cellular effects are accompanied by selective reduction of m.sup.6A levels on known leukaemogenic mRNAs and a decrease in their expression consistent with a translational defect. We demonstrate that pharmacological inhibition of METTL3 in vivo leads to impaired engraftment and prolonged survival in various mouse models of AML, specifically targeting key stem cell subpopulations of AML. Collectively, these results reveal the inhibition of METTL3 as a potential therapeutic strategy against AML, and provide proof of concept that the targeting of RNA-modifying enzymes represents a promising avenue for anticancer therapy. Treatment with a specific inhibitor of the N.sup.6-methyladenosine methyltransferase METTL3 leads to reduced growth of cancer cells, indicating the potential of approaches targeting RNA-modifying enzymes for anticancer therapy., Author(s): Eliza Yankova [sup.1] [sup.2] [sup.3] , Wesley Blackaby [sup.3] , Mark Albertella [sup.3] , Justyna Rak [sup.2] [sup.4] , Etienne De Braekeleer [sup.2] [sup.4] , Georgia Tsagkogeorga [sup.1] [sup.3] [...]

Published
2021
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5. PPM1D Mutations Drive Clonal Hematopoiesis in Response to Cytotoxic Chemotherapy

Author

Hsu, Joanne I., Dayaram, Tajhal, Tovy, Ayala, De Braekeleer, Etienne, Jeong, Mira, Wang, Feng, Zhang, Jianhua, Heffernan, Timothy P., Gera, Sonal, Kovacs, Jeffrey J., Marszalek, Joseph R., Bristow, Christopher, Yan, Yuanqing, Garcia-Manero, Guillermo, Kantarjian, Hagop, Vassiliou, George, Futreal, P. Andrew, Donehower, Lawrence A., Takahashi, Koichi, and Goodell, Margaret A.

Published
2018
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6. Publisher Correction: UTX-mediated enhancer and chromatin remodeling suppresses myeloid leukemogenesis through noncatalytic inverse regulation of ETS and GATA programs

Author

Gozdecka, Malgorzata, Meduri, Eshwar, Mazan, Milena, Tzelepis, Konstantinos, Dudek, Monika, Knights, Andrew J., Pardo, Mercedes, Yu, Lu, Choudhary, Jyoti S., Metzakopian, Emmanouil, Iyer, Vivek, Yun, Haiyang, Park, Naomi, Varela, Ignacio, Bautista, Ruben, Collord, Grace, Dovey, Oliver, Garyfallos, Dimitrios A., De Braekeleer, Etienne, Kondo, Saki, Cooper, Jonathan, Göttgens, Berthold, Bullinger, Lars, Northcott, Paul A., Adams, David, Vassiliou, George S., and Huntly, Brian J. P.

Published
2022
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8. UTX-mediated enhancer and chromatin remodeling suppresses myeloid leukemogenesis through noncatalytic inverse regulation of ETS and GATA programs

Author

Gozdecka, Malgorzata, Meduri, Eshwar, Mazan, Milena, Tzelepis, Konstantinos, Dudek, Monika, Knights, Andrew J., Pardo, Mercedes, Yu, Lu, Choudhary, Jyoti S., Metzakopian, Emmanouil, Iyer, Vivek, Yun, Haiyang, Park, Naomi, Varela, Ignacio, Bautista, Ruben, Collord, Grace, Dovey, Oliver, Garyfallos, Dimitrios A., De Braekeleer, Etienne, Kondo, Saki, Cooper, Jonathan, Göttgens, Berthold, Bullinger, Lars, Northcott, Paul A., Adams, David, Vassiliou, George S., and Huntly, Brian J. P.

Published
2018
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10. SRPK1 maintains acute myeloid leukemia through effects on isoform usage of epigenetic regulators including BRD4

Author

Tzelepis, Konstantinos, De Braekeleer, Etienne, Aspris, Demetrios, Barbieri, Isaia, Vijayabaskar, M. S., Liu, Wen-Hsin, Gozdecka, Malgorzata, Metzakopian, Emmanouil, Toop, Hamish D., Dudek, Monika, Robson, Samuel C., Hermida-Prado, Francisco, Yang, Yu Hsuen, Babaei-Jadidi, Roya, Garyfallos, Dimitrios A., Ponstingl, Hannes, Dias, Joao M. L., Gallipoli, Paolo, Seiler, Michael, Buonamici, Silvia, Vick, Binje, Bannister, Andrew J., Rad, Roland, Prinjha, Rab K., Marioni, John C., Huntly, Brian, Batson, Jennifer, Morris, Jonathan C., Pina, Cristina, Bradley, Allan, Jeremias, Irmela, Bates, David O., Yusa, Kosuke, Kouzarides, Tony, and Vassiliou, George S.

Published
2018
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21. Setbp1 Overexpression Acts in the Place of Class-Defining Somatic Mutations to Drive Mouse and Human FLT3-ITD-Mutant AMLs

Author

Pacharne, Suruchi, primary, Dovey, Oliver M., additional, Cooper, Jonathan L, additional, Gu, Muxin, additional, Baskar, Vijay, additional, Friedrich, Mathias J, additional, Gozdecka, Malgorzata, additional, Rajan, Sandeep S, additional, De Braekeleer, Etienne, additional, Barenboim, Maxim, additional, Collord, Grace, additional, Postingl, Hannes, additional, Bautista, Ruben, additional, Mazan, Milena, additional, Rad, Roland, additional, Tzelepis, Konstantinos, additional, Wright, Penny, additional, and Vassiliou, George S., additional

Published
2020
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22. Abstract 608: The MPS1 inhibitor S81694 is active in acute myeloid leukemia (AML)

Author

Kaci, Anna, primary, Adicéam, Emilie, additional, De Braekeleer, Etienne, additional, Garrido, Marine, additional, Berrou, Jeannig, additional, Dupont, Mélanie, additional, Djamai, Hanane, additional, Eclache, Virginie, additional, André, Baruchel, additional, Gardin, Claude, additional, Dombret, Hervé, additional, Burbridge, Mike, additional, and Braun, Thorsten, additional

Published
2020
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23. KAT7 is a genetic vulnerability of acute myeloid leukemias driven by MLL rearrangements

Author

Au, Yan Zi, primary, Gu, Muxin, additional, De Braekeleer, Etienne, additional, Gozdecka, Malgorzata, additional, Aspris, Demetrios, additional, Tarumoto, Yusuke, additional, Cooper, Jonathan, additional, Yu, Jason, additional, Ong, Swee Hoe, additional, Chen, Xi, additional, Tzelepis, Konstantinos, additional, Huntly, Brian J. P., additional, Vassiliou, George, additional, and Yusa, Kosuke, additional

Published
2020
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27. KAT7 is a genetic vulnerability of acute myeloid leukemias driven by MLL rearrangements

Author

70551381, 00813180, Au, Yan Zi, Gu, Muxin, De Braekeleer, Etienne, Gozdecka, Malgorzata, Aspris, Demetrios, Tarumoto, Yusuke, Cooper, Jonathan, Yu, Jason, Ong, Swee Hoe, Chen, Xi, Tzelepis, Konstantinos, Huntly, Brian J. P., Vassiliou, George, Yusa, Kosuke, 70551381, 00813180, Au, Yan Zi, Gu, Muxin, De Braekeleer, Etienne, Gozdecka, Malgorzata, Aspris, Demetrios, Tarumoto, Yusuke, Cooper, Jonathan, Yu, Jason, Ong, Swee Hoe, Chen, Xi, Tzelepis, Konstantinos, Huntly, Brian J. P., Vassiliou, George, and Yusa, Kosuke

Abstract

Histone acetyltransferases (HATs) catalyze the transfer of an acetyl group from acetyl-CoA to lysine residues of histones and play a central role in transcriptional regulation in diverse biological processes. Dysregulation of HAT activity can lead to human diseases including developmental disorders and cancer. Through genome-wide CRISPR-Cas9 screens, we identified several HATs of the MYST family as fitness genes for acute myeloid leukemia (AML). Here we investigate the essentiality of lysine acetyltransferase KAT7 in AMLs driven by the MLL-X gene fusions. We found that KAT7 loss leads to a rapid and complete loss of both H3K14ac and H4K12ac marks, in association with reduced proliferation, increased apoptosis, and differentiation of AML cells. Acetyltransferase activity of KAT7 is essential for the proliferation of these cells. Mechanistically, our data propose that acetylated histones provide a platform for the recruitment of MLL-fusion-associated adaptor proteins such as BRD4 and AF4 to gene promoters. Upon KAT7 loss, these factors together with RNA polymerase II rapidly dissociate from several MLL-fusion target genes that are essential for AML cell proliferation, including MEIS1, PBX3, and SENP6. Our findings reveal that KAT7 is a plausible therapeutic target for this poor prognosis AML subtype.

Published
2020

28. Pharmacological Inhibition of the RNA m6a Writer METTL3 As a Novel Therapeutic Strategy for Acute Myeloid Leukemia

Author

Tzelepis, Konstantinos, primary, De Braekeleer, Etienne, primary, Yankova, Eliza, primary, Rak, Justyna, primary, Aspris, Demetrios, primary, Domingues, Ana Filipa, primary, Fosbeary, Richard, primary, Hendrick, Alan, primary, Leggate, Dan, primary, Ofir-Rosenfeld, Yaara, primary, Sapetschnig, Alexandra, primary, Pina, Cristina, primary, Albertella, Mark, primary, Blackaby, Wesley, primary, Rausch, Oliver, primary, Vassiliou, George S., primary, and Kouzarides, Tony, primary

Published
2019
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29. The Nucleotide Kinase Nadk Is Required for ROS Detoxification and Constitutes a Metabolic Vulnerability of NOTCH1-Driven T-ALL

Author

De Braekeleer, Etienne, primary, Hsu, Joanne, additional, Hervieu, Celine, additional, Tzelepis, Konstantinos, additional, Indraccolo, Stefano, additional, Warren, Alan J., additional, Jeremias, Irmela, additional, Antoran, David Fernandez, additional, Jones, Phil H, additional, Goodell, Margaret A., additional, and Vassiliou, George S., additional

Published
2018
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30. High Prevalence of PPM1D Mutations in Therapy-Related AML/MDS Is Due to Context-Specific Clonal Hematopoiesis

Author

Hsu, Joanne, primary, Dayaram, Tajhal, additional, Tovy, Ayala, additional, De Braekeleer, Etienne, additional, Jeong, Mira, additional, Rogers, Jason H., additional, Wang, Feng, additional, Zhang, Jianhua, additional, Garcia-Manero, Guillermo, additional, Kantarjian, Hagop M., additional, Vassiliou, George S., additional, Futreal, Andrew, additional, Donehower, Lawrence, additional, Takahashi, Koichi, additional, and Goodell, Margaret, additional

Published
2018
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31. SETBP1overexpression acts in the place of class-defining mutations to drive FLT3-ITD–mutant AML

Author

Pacharne, Suruchi, Dovey, Oliver M., Cooper, Jonathan L., Gu, Muxin, Friedrich, Mathias J., Rajan, Sandeep S., Barenboim, Maxim, Collord, Grace, Vijayabaskar, M.S., Ponstingl, Hannes, De Braekeleer, Etienne, Bautista, Ruben, Mazan, Milena, Rad, Roland, Tzelepis, Konstantinos, Wright, Penny, Gozdecka, Malgorzata, and Vassiliou, George S.

Abstract

Advances in cancer genomics have revealed genomic classes of acute myeloid leukemia (AML) characterized by class-defining mutations, such as chimeric fusion genes or in genes such as NPM1, MLL, and CEBPA. These class-defining mutations frequently synergize with internal tandem duplications in FLT3(FLT3-ITDs) to drive leukemogenesis. However, ∼20% of FLT3-ITD–positive AMLs bare no class-defining mutations, and mechanisms of leukemic transformation in these cases are unknown. To identify pathways that drive FLT3-ITD mutant AML in the absence of class-defining mutations, we performed an insertional mutagenesis (IM) screening in Flt3-ITD mice, using Sleeping Beautytransposons. All mice developed acute leukemia (predominantly AML) after a median of 73 days. Analysis of transposon insertions in 38 samples from Flt3-ITD/IM leukemic mice identified recurrent integrations at 22 loci, including Setbp1(20/38), Ets1(11/38), Ash1l(8/38), Notch1(8/38), Erg(7/38), and Runx1(5/38). Insertions at Setbp1led exclusively to AML and activated a transcriptional program similar, but not identical, to those of NPM1-mutant and MLL-rearranged AMLs. Guide RNA targeting of Setbp1was highly detrimental to Flt3ITD/+/Setbp1IM+, but not to Flt3ITD/+/Npm1cA/+, AMLs. Also, analysis of RNA-sequencing data from hundreds of human AMLs revealed that SETBP1expression is significantly higher in FLT3-ITD AMLs lacking class-defining mutations. These findings propose that SETBP1overexpression collaborates with FLT3-ITD to drive a subtype of human AML. To identify genetic vulnerabilities of these AMLs, we performed genome-wide CRISPR-Cas9 screening in Flt3ITD/+/Setbp1IM+AMLs and identified potential therapeutic targets, including Kdm1a, Brd3, Ezh2, and Hmgcr. Our study gives new insights into epigenetic pathways that can drive AMLs lacking class-defining mutations and proposes therapeutic approaches against such cases.

Published
2021
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32. Using bacterial artificial chromosomes in leukemia research: the experience at the University Cytogenetics Laboratory in Brest, France

Author

De Braekeleer, Etienne, Douet-Guilbert, Nathalie, Basinko, Audrey, Morel, Frederic, Le Bris, Marie-Josee, Ferec, Claude, and De Braekeleer, Marc

Subjects
Usage, Physiological aspects, Research, Genetic aspects, DNA sequencing -- Usage -- Physiological aspects -- Research -- Genetic aspects, Leukemia -- Research -- Genetic aspects, Artificial chromosomes -- Physiological aspects -- Research -- Genetic aspects -- Usage, Nucleotide sequencing -- Usage -- Physiological aspects -- Research -- Genetic aspects
Abstract

1. Introduction Since chromosome banding techniques have been applied to the analysis of chromosomal aberrations in leukemia and cancer, several hundreds of recurring chromosomal breakpoints have been identified. They also [...], The development of the bacterial artificial chromosome (BAC) system was driven in part by the human genome project in order to construct genomic DNA libraries and physical maps for genomic sequencing. The availability of BAC clones has become a valuable tool for identifying cancer genes. We report here our experience in identifying genes located at breakpoints of chromosomal rearrangements and in defining the size and boundaries of deletions in hematological diseases. The methodology used in our laboratory consists of a three-step approach using conventional cytogenetics followed by FISH with commercial probes, then BAC clones. One limitation to the BAC system is that it can only accommodate inserts of up to 300 kb. As a consequence, analyzing the extent of deletions requires a large amount of material. Array comparative genomic hybridization (array-CGH) using a BAC/PAC system can be an alternative. However, this technique has limitations also, and it cannot be used to identify candidate genes at breakpoints of chromosomal rearrangements such as translocations, insertions, and inversions.

Published
2011
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33. A CRISPR Dropout Screen Identifies Genetic Vulnerabilities and Therapeutic Targets in Acute Myeloid Leukemia

Author

Tzelepis, Konstantinos, Koike-Yusa, Hiroko, De Braekeleer, Etienne, Li, Yilong, Metzakopian, Emmanouil, Dovey, Oliver M., Mupo, Annalisa, Grinkevich, Vera, Li, Meng, Mazan, Milena, Gozdecka, Malgorzata, Ohnishi, Shuhei, Cooper, Jonathan, Patel, Miten, McKerrell, Thomas, Chen, Bin, Domingues, Ana Filipa, Gallipoli, Paolo, Teichmann, Sarah, Ponstingl, Hannes, McDermott, Ultan, Saez-Rodriguez, Julio, Huntly, Brian J.P., Iorio, Francesco, Pina, Cristina, Vassiliou, George S., Yusa, Kosuke, Tzelepis, Konstantinos [0000-0002-4865-7648], Mupo, Annalisa [0000-0002-2771-0462], McKerrell, Thomas [0000-0003-4235-0650], Gallipoli, Paolo [0000-0001-7254-2253], Teichmann, Sarah [0000-0002-6294-6366], Huntly, Brian [0000-0003-0312-161X], Correia Antunes Pina, Cristina [0000-0002-2575-6301], Vassiliou, George [0000-0003-4337-8022], and Apollo - University of Cambridge Repository

Subjects
Adult, Resource, Apoptosis, genetic vulnerability, KAT2A, Genetic vulnerability, acute myeloid leukemia, Genetic screen, AML, Cell Line, Tumor, hemic and lymphatic diseases, Humans, Clustered Regularly Interspaced Short Palindromic Repeats, Genetic Testing, Molecular Targeted Therapy, lcsh:QH301-705.5, neoplasms, health care economics and organizations, Cell Proliferation, Histone Acetyltransferases, Acute myeloid leukemia, Reproducibility of Results, Cell Differentiation, Leukemia, Myeloid, Acute, MB-3, lcsh:Biology (General), genetic screen, CRISPR, KAT2A MB-3
Abstract

Summary Acute myeloid leukemia (AML) is an aggressive cancer with a poor prognosis, for which mainstream treatments have not changed for decades. To identify additional therapeutic targets in AML, we optimize a genome-wide clustered regularly interspaced short palindromic repeats (CRISPR) screening platform and use it to identify genetic vulnerabilities in AML cells. We identify 492 AML-specific cell-essential genes, including several established therapeutic targets such as DOT1L, BCL2, and MEN1, and many other genes including clinically actionable candidates. We validate selected genes using genetic and pharmacological inhibition, and chose KAT2A as a candidate for downstream study. KAT2A inhibition demonstrated anti-AML activity by inducing myeloid differentiation and apoptosis, and suppressed the growth of primary human AMLs of diverse genotypes while sparing normal hemopoietic stem-progenitor cells. Our results propose that KAT2A inhibition should be investigated as a therapeutic strategy in AML and provide a large number of genetic vulnerabilities of this leukemia that can be pursued in downstream studies., Graphical Abstract, Highlights • Optimized CRISPR platform for identification of genome-wide genetic vulnerabilities • Catalog of genetic vulnerabilities in acute myeloid leukemia cell lines • KAT2A inhibition induces myeloid differentiation and apoptosis • KAT2A inhibition arrests the growth of primary AML cells, but not of normal progenitors, Tzelepis et al. optimize a CRISPR-Cas9-based platform for the performance of genome-wide recessive screens and apply it to identify genetic vulnerabilities of human AML cells. They identify several known therapeutic targets including BRD4, DOT1L, and MEN1, and numerous additional candidates. They provide data proposing KAT2A as a potential therapeutic target.

Published
2016
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34. SRPK1 Is a Therapeutic Vulnerability in Acute Myeloid Leukemia through Its Effects on Alternative Isoforms of Epigenetic Regulators Including BRD4

Author

Tzelepis, Konstantinos, primary, De Braekeleer, Etienne, additional, Barbieri, Isaia, additional, Baskar, Vijay, additional, Aspris, Demetrios, additional, Prado, Francisco Hermida, additional, Gozdecka, Malgorzata, additional, Dudek, Monika, additional, Postingl, Hannes, additional, Bates, David, additional, Bannister, Andrew, additional, Huntly, Brian J.P, additional, Pina, Cristina, additional, Bradley, Allan, additional, Yusa, Kosuke, additional, Kouzarides, Tony, additional, and Vassiliou, George S., additional

Published
2017
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37. t(11;22)(q13;q13) HRASLS5/PHF21B

Author

Douet-Guilbert, Nathalie, primary, De Braekeleer, Etienne, additional, Tous, Corinne, additional, Guéganic, Nadia, additional, and Basinko, Audrey, additional

Published
2017
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38. inv(3)(q21q26) RPN1/MECOM

Author

De Braekeleer, Etienne, primary, Douet-Guilbert, Nathalie, additional, Le Bris, Marie-José, additional, Basinko, Audrey, additional, and Morel, Frédéric, additional

Published
2017
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40. A CRISPR Dropout Screen Identifies Genetic Vulnerabilities and Therapeutic Targets in Acute Myeloid Leukemia

Author

Tzelepis, Konstantinos, primary, Koike-Yusa, Hiroko, additional, De Braekeleer, Etienne, additional, Li, Yilong, additional, Metzakopian, Emmanouil, additional, Dovey, Oliver M., additional, Mupo, Annalisa, additional, Grinkevich, Vera, additional, Li, Meng, additional, Mazan, Milena, additional, Gozdecka, Malgorzata, additional, Ohnishi, Shuhei, additional, Cooper, Jonathan, additional, Patel, Miten, additional, McKerrell, Thomas, additional, Chen, Bin, additional, Domingues, Ana Filipa, additional, Gallipoli, Paolo, additional, Teichmann, Sarah, additional, Ponstingl, Hannes, additional, McDermott, Ultan, additional, Saez-Rodriguez, Julio, additional, Huntly, Brian J.P., additional, Iorio, Francesco, additional, Pina, Cristina, additional, Vassiliou, George S., additional, and Yusa, Kosuke, additional

Published
2016
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42. A Crispr/Cas9 Drop-out Screen Identifies Genome-Wide Genetic Valnerubilities in Acute Myeloid Leukaemia

Author

Tzelepis, Konstantinos, primary, Koike-Yusa, Hiroko, additional, De Braekeleer, Etienne, additional, Li, Yilong, additional, Metzakopian, Emmanouil, additional, Dovey, Oliver M., additional, Mupo, Annalisa, additional, Grinkevich, Vera, additional, Mazan, Milena M., additional, Gozdecka, Malgorzata, additional, Cooper, Jonathan L., additional, Patel, Miten, additional, McKerrell, Thomas David Hardman, additional, Chen, Bin, additional, Ponstingl, Hannes, additional, Huntly, Brian J.P, additional, McDermott, Ultan, additional, Saez-Rodriguez, Julio, additional, Iorio, Francesco, additional, Yusa, Kosuke, additional, and Vassiliou, George S., additional

Published
2015
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46. Promoter-bound METTL3 maintains myeloid leukaemia by m6A-dependent translation control.

Author

Barbieri, Isaia, Tzelepis, Konstantinos, Pandolfini, Luca, Shi, Junwei, Millán-Zambrano, Gonzalo, Robson, Samuel C., Aspris, Demetrios, Migliori, Valentina, Bannister, Andrew J., Han, Namshik, De Braekeleer, Etienne, Ponstingl, Hannes, Hendrick, Alan, Vakoc, Christopher R., Vassiliou, George S., and Kouzarides, Tony

Abstract

N6-methyladenosine (m6A) is an abundant internal RNA modification in both coding and non-coding RNAs that is catalysed by the METTL3-METTL14 methyltransferase complex. However, the specific role of these enzymes in cancer is still largely unknown. Here we define a pathway that is specific for METTL3 and is implicated in the maintenance of a leukaemic state. We identify METTL3 as an essential gene for growth of acute myeloid leukaemia cells in two distinct genetic screens. Downregulation of METTL3 results in cell cycle arrest, differentiation of leukaemic cells and failure to establish leukaemia in immunodeficient mice. We show that METTL3, independently of METTL14, associates with chromatin and localizes to the transcriptional start sites of active genes. The vast majority of these genes have the CAATT-box binding protein CEBPZ present at the transcriptional start site, and this is required for recruitment of METTL3 to chromatin. Promoter-bound METTL3 induces m6A modification within the coding region of the associated mRNA transcript, and enhances its translation by relieving ribosome stalling. We show that genes regulated by METTL3 in this way are necessary for acute myeloid leukaemia. Together, these data define METTL3 as a regulator of a chromatin-based pathway that is necessary for maintenance of the leukaemic state and identify this enzyme as a potential therapeutic target for acute myeloid leukaemia. [ABSTRACT FROM AUTHOR]

Published
2017
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47. Prognostic impact of p15 gene aberrations in acute leukemia.

Author

De Braekeleer, Marc, Douet-Guilbert, Nathalie, and De Braekeleer, Etienne

Subjects
CHROMOSOME abnormalities, ACUTE leukemia, CELL cycle, KINASES, PROGENITOR cells
Abstract

Thep15gene (also known asCDKN2B,INK4B,p15INK4B), located in band 9p21, encodes a protein that induces a G1-phase cell cycle arrest through inhibition of CDK4/6 (cyclin-dependent kinase 4/6). It also plays an important role in the regulation of cellular commitment of hematopoietic progenitor cells and myeloid cell differentiation.p15can be silenced by several mechanisms, including deletion and hypermethylation of its promoter. Homozygousp15deletion is rare in acute myeloblastic leukemia (AML) and myelodysplastic syndromes (MDS) but frequent in acute lymphoblastic leukemia (ALL). On the contrary, methylation of thep15promoter is identified in some 50% of the patients with AML and MDS, but is less frequent in ALL. The analysis of the 28 studies available in the literature revealed conflicting results (unfavorable, favorable or no impact) that can be due, at least in part, to methodological and/or biological pitfalls. Among those, are the heterogeneity of the methylation patterns of thep15gene and the lack of a comprehensive analysis including transcriptional and translational inactivation that have major impact on its expression. Therefore, detection of thep15mRNA expression (quantitative or not) may represent a more appropriate method to determine the prognostic impact of thep15gene. [ABSTRACT FROM AUTHOR]

Published
2017
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