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152. 14q32 rearrangements deregulating BCL11Bmark a distinct subgroup of T-lymphoid and myeloid immature acute leukemia

Author

Di Giacomo, Danika, La Starza, Roberta, Gorello, Paolo, Pellanera, Fabrizia, Kalender Atak, Zeynep, De Keersmaecker, Kim, Pierini, Valentina, Harrison, Christine J., Arniani, Silvia, Moretti, Martina, Testoni, Nicoletta, De Santis, Giovanna, Roti, Giovanni, Matteucci, Caterina, Bassan, Renato, Vandenberghe, Peter, Aerts, Stein, Cools, Jan, Bornhauser, Beat, Bourquin, Jean-Pierre, Piazza, Rocco, and Mecucci, Cristina

Abstract

Acute leukemias (ALs) of ambiguous lineage are a heterogeneous group of high-risk leukemias characterized by coexpression of myeloid and lymphoid markers. In this study, we identified a distinct subgroup of immature acute leukemias characterized by a broadly variable phenotype, covering acute myeloid leukemia (AML, M0 or M1), T/myeloid mixed-phenotype acute leukemia (T/M MPAL), and early T-cell precursor acute lymphoblastic leukemia (ETP-ALL). Rearrangements at 14q32/BCL11Bare the cytogenetic hallmark of this entity. In our screening of 915 hematological malignancies, there were 202 AML and 333 T-cell acute lymphoblastic leukemias (T-ALL: 58, ETP; 178, non-ETP; 8, T/M MPAL; 89, not otherwise specified). We identified 20 cases of immature leukemias (4% of AML and 3.6% of T-ALL), harboring 4 types of 14q32/BCL11Btranslocations: t(2,14)(q22.3;q32) (n = 7), t(6;14)(q25.3;q32) (n = 9), t(7;14)(q21.2;q32) (n = 2), and t(8;14)(q24.2;q32) (n = 2). The t(2;14) produced a ZEB2-BCL11Bfusion transcript, whereas the other 3 rearrangements displaced transcriptionally active enhancer sequences close to BCL11Bwithout producing fusion genes. All translocations resulted in the activation of BCL11B, a regulator of T-cell differentiation associated with transcriptional corepressor complexes in mammalian cells. The expression of BCL11Bbehaved as a disease biomarker that was present at diagnosis, but not in remission. Deregulation of BCL11Bco-occurred with variants at FLT3and at epigenetic modulators, most frequently the DNMT3A, TET2, and/or WT1genes. Transcriptome analysis identified a specific expression signature, with significant downregulation of BCL11B targets, and clearly separating BCL11BAL from AML, T-ALL, and ETP-ALL. Remarkably, an ex vivo drug-sensitivity profile identified a panel of compounds with effective antileukemic activity.

Published
2021
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153. 14q32 rearrangements deregulating BCL11B mark a distinct subgroup of T-lymphoid and myeloid immature acute leukemia

Author

Di Giacomo, Danika, La Starza, Roberta, Gorello, Paolo, Pellanera, Fabrizia, Kalender Atak, Zeynep, De Keersmaecker, Kim, Pierini, Valentina, Harrison, Christine J., Arniani, Silvia, Moretti, Martina, Testoni, Nicoletta, De Santis, Giovanna, Roti, Giovanni, Matteucci, Caterina, Bassan, Renato, Vandenberghe, Peter, Aerts, Stein, Cools, Jan, Bornhauser, Beat, Bourquin, Jean-Pierre, Piazza, Rocco, and Mecucci, Cristina

Abstract

Acute leukemias (ALs) of ambiguous lineage are a heterogeneous group of high-risk leukemias characterized by coexpression of myeloid and lymphoid markers. In this study, we identified a distinct subgroup of immature acute leukemias characterized by a broadly variable phenotype, covering acute myeloid leukemia (AML, M0 or M1), T/myeloid mixed-phenotype acute leukemia (T/M MPAL), and early T-cell precursor acute lymphoblastic leukemia (ETP-ALL). Rearrangements at 14q32/BCL11B are the cytogenetic hallmark of this entity. In our screening of 915 hematological malignancies, there were 202 AML and 333 T-cell acute lymphoblastic leukemias (T-ALL: 58, ETP; 178, non-ETP; 8, T/M MPAL; 89, not otherwise specified). We identified 20 cases of immature leukemias (4% of AML and 3.6% of T-ALL), harboring 4 types of 14q32/BCL11B translocations: t(2,14)(q22.3;q32) (n = 7), t(6;14)(q25.3;q32) (n = 9), t(7;14)(q21.2;q32) (n = 2), and t(8;14)(q24.2;q32) (n = 2). The t(2;14) produced a ZEB2-BCL11B fusion transcript, whereas the other 3 rearrangements displaced transcriptionally active enhancer sequences close to BCL11B without producing fusion genes. All translocations resulted in the activation of BCL11B, a regulator of T-cell differentiation associated with transcriptional corepressor complexes in mammalian cells. The expression of BCL11B behaved as a disease biomarker that was present at diagnosis, but not in remission. Deregulation of BCL11B co-occurred with variants at FLT3 and at epigenetic modulators, most frequently the DNMT3A, TET2, and/or WT1 genes. Transcriptome analysis identified a specific expression signature, with significant downregulation of BCL11B targets, and clearly separating BCL11B AL from AML, T-ALL, and ETP-ALL. Remarkably, an ex vivo drug-sensitivity profile identified a panel of compounds with effective antileukemic activity.

Published
2021
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157. Genome-wide association study identifies susceptibility loci for B-cell childhood acute lymphoblastic leukemia

Author

Vijayakrishnan, Jayaram, Studd, James, Broderick, Peter, Kinnersley, Ben, Holroyd, Amy, Law, Philip J., Kumar, Rajiv, Allan, James M., Harrison, Christine J., Moorman, Anthony V., Vora, Ajay, Roman, Eve, Rachakonda, Sivaramakrishna, Kinsey, Sally E., Sheridan, Eamonn, Thompson, Pamela D., Irving, Julie A., Koehler, Rolf, Hoffmann, Per, Nöthen, Markus M., Heilmann-Heimbach, Stefanie, Jöckel, Karl-Heinz, Easton, Douglas F., Pharaoh, Paul D. P., Dunning, Alison M., Peto, Julian, Canzian, Frederico, Swerdlow, Anthony, Eeles, Rosalind A., Kote-Jarai, ZSofia, Muir, Kenneth, Pashayan, Nora, Greaves, Mel, Zimmerman, Martin, Bartram, Claus R., Schrappe, Martin, Stanulla, Martin, Hemminki, Kari, and Houlston, Richard S.

Subjects
Male, Oncogene Proteins, Fusion, Glycosyltransferases, Prognosis, Polymorphism, Single Nucleotide, Article, HLA Antigens, Risk Factors, Child, Preschool, Precursor B-Cell Lymphoblastic Leukemia-Lymphoma, Core Binding Factor Alpha 2 Subunit, Humans, Female, Genetic Predisposition to Disease, Child, Author Correction, Genome-Wide Association Study
Abstract

Genome-wide association studies (GWAS) have advanced our understanding of susceptibility to B-cell precursor acute lymphoblastic leukemia (BCP-ALL); however, much of the heritable risk remains unidentified. Here, we perform a GWAS and conduct a meta-analysis with two existing GWAS, totaling 2442 cases and 14,609 controls. We identify risk loci for BCP-ALL at 8q24.21 (rs28665337, P = 3.86 × 10−9, odds ratio (OR) = 1.34) and for ETV6-RUNX1 fusion-positive BCP-ALL at 2q22.3 (rs17481869, P = 3.20 × 10−8, OR = 2.14). Our findings provide further insights into genetic susceptibility to ALL and its biology., While GWAS have uncovered susceptibility loci for B-cell precursor acute lymphoblastic leukemia (BCP-ALL), much of the heritable risk remains undiscovered. Here, the authors perform a meta-analysis of two existing BCP-ALL GWAS together with an unpublished GWAS to identify risk loci at 8q24.21 and 2q22.3.

Published
2017

159. SSBP2-CSF1Ris a recurrent fusion in B-lineage acute lymphoblastic leukemia with diverse genetic presentation and variable outcome

Author

Schwab, Claire, Roberts, Kathryn, Boer, Judith M., Göhring, Gudrun, Steinemann, Doris, Vora, Ajay, Macartney, Christine, Hough, Rachael, Thorn, Zoe, Dillon, Richard, Escherich, Gabriele, Cazzaniga, Giovanni, Schlegelberger, Brigitte, Loh, Mignon, den Boer, Monique L., Moorman, Anthony V., and Harrison, Christine J.

Published
2021
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163. Genetic characterization and therapeutic targeting of MYC ‐rearranged T cell acute lymphoblastic leukaemia

Author

Milani, Gloria, primary, Matthijssens, Filip, additional, Van Loocke, Wouter, additional, Durinck, Kaat, additional, Roels, Juliette, additional, Peirs, Sofie, additional, Thénoz, Morgan, additional, Pieters, Tim, additional, Reunes, Lindy, additional, Lintermans, Beatrice, additional, Vandamme, Niels, additional, Lammens, Tim, additional, Van Roy, Nadine, additional, Van Nieuwerburgh, Filip, additional, Deforce, Dieter, additional, Schwab, Claire, additional, Raimondi, Susana, additional, Dalla Pozza, Luciano, additional, Carroll, Andrew J., additional, De Moerloose, Barbara, additional, Benoit, Yves, additional, Goossens, Steven, additional, Berx, Geert, additional, Harrison, Christine J., additional, Basso, Giuseppe, additional, Cavé, Hélène, additional, Sutton, Rosemary, additional, Asnafi, Vahid, additional, Meijerink, Jules, additional, Mullighan, Charles, additional, Loh, Mignon, additional, and Van Vlierberghe, Pieter, additional

Published
2018
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164. The ribosomal RPL10 R98S mutation drives IRES-dependent BCL-2 translation in T-ALL

Author

Kampen, Kim R., primary, Sulima, Sergey O., additional, Verbelen, Benno, additional, Girardi, Tiziana, additional, Vereecke, Stijn, additional, Rinaldi, Gianmarco, additional, Verbeeck, Jelle, additional, Op de Beeck, Joyce, additional, Uyttebroeck, Anne, additional, Meijerink, Jules P. P., additional, Moorman, Anthony V., additional, Harrison, Christine J., additional, Spincemaille, Pieter, additional, Cools, Jan, additional, Cassiman, David, additional, Fendt, Sarah-Maria, additional, Vermeersch, Pieter, additional, and De Keersmaecker, Kim, additional

Published
2018
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166. Dynamic clonal progression in xenografts of acute lymphoblastic leukemia with intrachromosomal amplification of chromosome 21

Author

Sinclair, Paul. B., primary, Blair, Helen H., additional, Ryan, Sarra L., additional, Buechler, Lars, additional, Cheng, Joanna, additional, Clayton, Jake, additional, Hanna, Rebecca, additional, Hollern, Shaun, additional, Hawking, Zoe, additional, Bashton, Matthew, additional, Schwab, Claire J., additional, Jones, Lisa, additional, Russell, Lisa J., additional, Marr, Helen, additional, Carey, Peter, additional, Halsey, Christina, additional, Heidenreich, Olaf, additional, Moorman, Anthony V., additional, and Harrison, Christine J., additional

Published
2018
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167. Genotype-Specific Minimal Residual Disease Interpretation Improves Stratification in Pediatric Acute Lymphoblastic Leukemia

Author

O’Connor, David, primary, Enshaei, Amir, additional, Bartram, Jack, additional, Hancock, Jeremy, additional, Harrison, Christine J., additional, Hough, Rachael, additional, Samarasinghe, Sujith, additional, Schwab, Claire, additional, Vora, Ajay, additional, Wade, Rachel, additional, Moppett, John, additional, Moorman, Anthony V., additional, and Goulden, Nick, additional

Published
2018
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168. Clinical characteristics and outcomes of B-ALL with ZNF384rearrangements: a retrospective analysis by the Ponte di Legno Childhood ALL Working Group

Author

Hirabayashi, Shinsuke, Butler, Ellie R., Ohki, Kentaro, Kiyokawa, Nobutaka, Bergmann, Anke K., Möricke, Anja, Boer, Judith M., Cavé, Hélène, Cazzaniga, Giovanni, Yeoh, Allen Eng Juh, Sanada, Masashi, Imamura, Toshihiko, Inaba, Hiroto, Mullighan, Charles, Loh, Mignon L., Norén-Nyström, Ulrika, Pastorczak, Agata, Shih, Lee-Yung, Zaliova, Marketa, Pui, Ching-Hon, Haas, Oskar A., Harrison, Christine J., Moorman, Anthony V., and Manabe, Atsushi

Published
2021
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169. Digital Multiplex Ligation-Dependent Probe Amplification for Detection of Key Copy Number Alterations in T- and B-Cell Lymphoblastic Leukemia

Author

Benard-Slagter, Anne, primary, Zondervan, Ilse, additional, de Groot, Karel, additional, Ghazavi, Farzaneh, additional, Sarhadi, Virinder, additional, Van Vlierberghe, Pieter, additional, De Moerloose, Barbara, additional, Schwab, Claire, additional, Vettenranta, Kim, additional, Harrison, Christine J., additional, Knuutila, Sakari, additional, Schouten, Jan, additional, Lammens, Tim, additional, and Savola, Suvi, additional

Published
2017
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170. Intragenic amplification of PAX5: a novel subgroup in B-cell precursor acute lymphoblastic leukemia?

Author

Schwab, Claire, primary, Nebral, Karin, additional, Chilton, Lucy, additional, Leschi, Cristina, additional, Waanders, Esmé, additional, Boer, Judith M., additional, Žaliová, Markéta, additional, Sutton, Rosemary, additional, Öfverholm, Ingegerd Ivanov, additional, Ohki, Kentaro, additional, Yamashita, Yuka, additional, Groeneveld-Krentz, Stefanie, additional, Froňková, Eva, additional, Bakkus, Marleen, additional, Tchinda, Joelle, additional, Barbosa, Thayana da Conceição, additional, Fazio, Grazia, additional, Mlynarski, Wojciech, additional, Pastorczak, Agata, additional, Cazzaniga, Giovanni, additional, Pombo-de-Oliveira, Maria S., additional, Trka, Jan, additional, Kirschner-Schwabe, Renate, additional, Imamura, Toshihiko, additional, Barbany, Gisela, additional, Stanulla, Martin, additional, Attarbaschi, Andishe, additional, Panzer-Grümayer, Renate, additional, Kuiper, Roland P., additional, den Boer, Monique L., additional, Cavé, Hélène, additional, Moorman, Anthony V., additional, Harrison, Christine J., additional, and Strehl, Sabine, additional

Published
2017
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171. Use of Minimal Residual Disease Assessment to Redefine Induction Failure in Pediatric Acute Lymphoblastic Leukemia

Author

O’Connor, David, primary, Moorman, Anthony V., additional, Wade, Rachel, additional, Hancock, Jeremy, additional, Tan, Ronald M.R., additional, Bartram, Jack, additional, Moppett, John, additional, Schwab, Claire, additional, Patrick, Katharine, additional, Harrison, Christine J., additional, Hough, Rachael, additional, Goulden, Nick, additional, Vora, Ajay, additional, and Samarasinghe, Sujith, additional

Published
2017
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172. Characterisation of the genomic landscape of CRLF2‐rearranged acute lymphoblastic leukemia

Author

Russell, Lisa J., primary, Jones, Lisa, additional, Enshaei, Amir, additional, Tonin, Stefano, additional, Ryan, Sarra L., additional, Eswaran, Jeyanthy, additional, Nakjang, Sirintra, additional, Papaemmanuil, Elli, additional, Tubio, Jose M. C., additional, Fielding, Adele K., additional, Vora, Ajay, additional, Campbell, Peter J., additional, Moorman, Anthony V., additional, and Harrison, Christine J., additional

Published
2017
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175. Epigenetic landscape correlates with genetic subtype but does not predict outcome in childhood acute lymphoblastic leukemia

Author

Gabriel, Alem S, Lafta, Fadhel M, Schwalbe, Edward C, Nakjang, Sirintra, Cockell, Simon J, Iliasova, Alice, Enshaei, Amir, Schwab, Claire, Rand, Vikki, Clifford, Steven C, Kinsey, Sally E, Mitchell, Chris D, Vora, Ajay, Harrison, Christine J, Moorman, Anthony V, and Strathdee, Gordon

Subjects
Epigenomics, Oncogene Proteins, Fusion, B100, 450K, Recurrence, Proto-Oncogene Proteins, hemic and lymphatic diseases, Basic Helix-Loop-Helix Transcription Factors, Humans, Child, childhood, relapse, Proto-Oncogene Proteins c-ets, Genome, Human, Pre-B-Cell Leukemia Transcription Factor 1, Infant, DNA Methylation, Precursor Cell Lymphoblastic Leukemia-Lymphoma, Prognosis, DNA-Binding Proteins, Repressor Proteins, Child, Preschool, Core Binding Factor Alpha 2 Subunit, biomarker, CpG Islands, methylation, ALL, Research Paper
Abstract

Although children with acute lymphoblastic leukemia (ALL) generally have a good outcome, some patients do relapse and survival following relapse is poor. Altered DNA methylation is highly prevalent in ALL and raises the possibility that DNA methylation-based biomarkers could predict patient outcome. In this study, genome-wide methylation analysis, using the Illumina Infinium HumanMethylation450 BeadChip platform, was carried out on 52 diagnostic patient samples from 4 genetic subtypes [ETV6-RUNX1, high hyperdiploidy (HeH), TCF3-PBX1 and dic(9;20)(p11-13;q11)] in a 1:1 case-control design with patients who went on to relapse (as cases) and patients achieving long-term remission (as controls). Pyrosequencing assays for selected loci were used to confirm the array-generated data. Non-negative matrix factorization consensus clustering readily clustered samples according to genetic subgroups and gene enrichment pathway analysis suggested that this is in part driven by epigenetic disruption of subtype specific signaling pathways. Multiple bioinformatics approaches (including bump hunting and individual locus analysis) were used to identify CpG sites or regions associated with outcome. However, no associations with relapse were identified. Our data revealed that ETV6-RUNX1 and dic(9;20) subtypes were mostly associated with hypermethylation; conversely, TCF3-PBX1 and HeH were associated with hypomethylation. We observed significant enrichment of the neuroactive ligand-receptor interaction pathway in TCF3-PBX1 as well as an enrichment of genes involved in immunity and infection pathways in ETV6-RUNX1 subtype. Taken together, our results suggest that altered DNA methylation may have differential impacts in distinct ALL genetic subtypes.

Published
2015

176. Design of a Comprehensive Fluorescence in SituHybridization Assay for Genetic Classification of T-Cell Acute Lymphoblastic Leukemia

Author

La Starza, Roberta, Pierini, Valentina, Pierini, Tiziana, Nofrini, Valeria, Matteucci, Caterina, Arniani, Silvia, Moretti, Martina, Lema Fernandez, Anair G., Pellanera, Fabrizia, Di Giacomo, Danika, Storlazzi, Tiziana C., Vitale, Antonella, Gorello, Paolo, Sammarelli, Gabriella, Roti, Giovanni, Basso, Giuseppe, Chiaretti, Sabina, Foà, Robin, Schwab, Claire, Harrison, Christine J., Van Vlierberghe, Pieter, and Mecucci, Cristina

Abstract

T-cell acute lymphoblastic leukemia (T-ALL) results from deregulation of a number of genes via multiple genomic mechanisms. We designed a comprehensive fluorescence in situhybridization (CI-FISH) assay that consists of genomic probes to simultaneously investigate oncogenes and oncosuppressors recurrently involved in chromosome rearrangements in T-ALL, which was applied to 338 T-ALL cases. CI-FISH provided genetic classification into one of the well-defined genetic subgroups (ie, TAL/LMO, HOXA, TLX3, TLX1, NKX2-1/2-2, or MEF2C) in 80% of cases. Two patients with translocations of the LMO3transcription factor were identified, suggesting that LMO3activation may serve as an alternative to LMO1/LMO2activation in the pathogenesis of this disease. Moreover, intrachromosomal rearrangements that involved the 10q24 locus were found as a new mechanism of TLX1activation. An unequal distribution of cooperating genetic defects was found among the six genetic subgroups. Interestingly, deletions that targeted TCF7or TP53were exclusively found in HOXAT-ALL, LEF1defects were prevalent in NKX2-1rearranged patients, CASP8AP2and PTENalterations were significantly enriched in TAL/LMOleukemias, and PTPN2and NUP214-ABL1abnormalities occurred in TLX1/TLX3. This work convincingly shows that CI-FISH is a powerful tool to define genetic heterogeneity of T-ALL, which may be applied as a rapid and accurate diagnostic test.

Published
2020
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177. Outcome of Children With Hypodiploid Acute Lymphoblastic Leukemia: A Retrospective Multinational Study.

Author

Pui, Ching-Hon, Rebora, Paola, Schrappe, Martin, Attarbaschi, Andishe, Baruchel, Andre, Basso, Giuseppe, Cavé, Hélène, Elitzur, Sarah, Koh, Katsuyoshi, Liu, Hsi-Che, Paulsson, Kajsa, Pieters, Rob, Silverman, Lewis B., Stary, Jan, Vora, Ajay, Yeoh, Allen, Harrison, Christine J., Valsecchi, Maria Grazia, and Ponte di Legno Childhood ALL Working Group

Published
2019
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178. Clinical Impact of Additional Cytogenetic Aberrations, cKIT and RAS Mutations, and Treatment Elements in Pediatric t(8;21)-AML: Results From an International Retrospective Study by the International Berlin-Frankfurt-Münster Study Group

Author

Klein, Kim, primary, Kaspers, Gertjan, additional, Harrison, Christine J., additional, Beverloo, H. Berna, additional, Reedijk, Ardine, additional, Bongers, Mathilda, additional, Cloos, Jacqueline, additional, Pession, Andrea, additional, Reinhardt, Dirk, additional, Zimmerman, Martin, additional, Creutzig, Ursula, additional, Dworzak, Michael, additional, Alonzo, Todd, additional, Johnston, Donna, additional, Hirsch, Betsy, additional, Zapotocky, Michal, additional, De Moerloose, Barbara, additional, Fynn, Alcira, additional, Lee, Vincent, additional, Taga, Takashi, additional, Tawa, Akio, additional, Auvrignon, Anne, additional, Zeller, Bernward, additional, Forestier, Erik, additional, Salgado, Carmen, additional, Balwierz, Walentyna, additional, Popa, Alexander, additional, Rubnitz, Jeffrey, additional, Raimondi, Susana, additional, and Gibson, Brenda, additional

Published
2015
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179. The 9p21.3 risk of childhood acute lymphoblastic leukaemia is explained by a rare high-impact variant in CDKN2A

Author

Vijayakrishnan, Jayaram, primary, Henrion, Marc, additional, Moorman, Anthony V., additional, Fiege, Bettina, additional, Kumar, Rajiv, additional, Inacio da Silva Filho, Miguel, additional, Holroyd, Amy, additional, Koehler, Rolf, additional, Thomsen, Hauke, additional, Irving, Julie A., additional, Allan, James M., additional, Lightfoot, Tracy, additional, Roman, Eve, additional, Kinsey, Sally E., additional, Sheridan, Eamonn, additional, Thompson, Pamela D., additional, Hoffmann, Per, additional, Nöthen, Markus M., additional, Mühleisen, Thomas W., additional, Eisele, Lewin, additional, Bartram, Claus R., additional, Schrappe, Martin, additional, Greaves, Mel, additional, Hemminki, Kari, additional, Harrison, Christine J., additional, Stanulla, Martin, additional, and Houlston, Richard S., additional

Published
2015
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182. IKZF1Deletions with COBLBreakpoints Are Not Driven by RAG-Mediated Recombination Events in Acute Lymphoblastic Leukemia

Author

Lopes, Bruno A., Meyer, Claus, Barbosa, Thayana C., Poubel, Caroline P., Mansur, Marcela B., Duployez, Nicolas, Bashton, Matthew, Harrison, Christine J., zur Stadt, Udo, Horstmann, Martin, Pombo-de-Oliveira, Maria S., Palmi, Chiara, Cazzaniga, Gianni, Venn, Nicola C., Sutton, Rosemary, Alonso, Cristina N., Tsaur, Grigory, Gupta, Sanjeev K., Bakhshi, Sameer, Marschalek, Rolf, and Emerenciano, Mariana

Abstract

IKZF1deletion (ΔIKZF1) is an important predictor of relapse in both childhood and adult B-cell precursor acute lymphoblastic leukemia (B-ALL). Previously, we revealed that COBLis a hotspot for breakpoints in leukemia and could promote IKZF1deletions. Through an international collaboration, we provide a detailed genetic and clinical picture of B-ALL with COBLrearrangements (COBL-r). Patients with B-ALL and IKZF1deletion (n = 133) were included. IKZF1∆1-8 were associated with large alterations within chromosome 7: monosomy 7 (18%), isochromosome 7q (10%), 7p loss (19%), and interstitial deletions (53%). The latter included COBL-r, which were found in 12% of the IKZF1∆1-8 cohort. Patients with COBL-r are mostly classified as intermediate cytogenetic risk and frequently harbor ETV6, PAX5, CDKN2A/Bdeletions. Overall, 56% of breakpoints were located within COBLintron 5. Cryptic recombination signal sequence motifs were broadly distributed within the sequence of COBL, and no enrichment for the breakpoint cluster region was found. In summary, a diverse spectrum of alterations characterizes ΔIKZF1and they also include deletion breakpoints within COBL. We confirmed that COBLis a hotspot associated with ΔIKZF1, but these rearrangements are not driven by RAG-mediated recombination.

Published
2019
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184. Translocation t(6;9)(p22;q34)/DEK-NUP214 rearranged Pediatric AML::A Retrospective international Study

Author

Sandahl, Julie Damgaard, Coenen, Eva A., Forestier, Erik, Harbott, Jochen, Johansson, Bertil, Kerndrup, Gitte Birk, Adachi, Souichi, Auvrignon, Anne, Beverloo, H. Berna, Chilton, Lucy, de Hass, Valerie, Harrison, Christine J, Inaba, Hiroto, Kaspers, Gertjan J. L., Liang, Der-Cherng, Lin, Kuo-Sin, Masetti, Riccardo, Perot, Christine, Pession, Andrea, Raimondi, Susana C., Reinhardt, Katarina, Tomizawa, Daisuke, von Neuhoff, Nils, Zecca, Marco, van den Heuvel-Eibrink, Marry M., and Hasle, Henrik

Published
2012

185. Pediatric Acute Myeloid Leukemia with t(8;16)(p11;p13): A Distinct Clinical and Biological Entity.:Results of a Collaborative Stydy by the International Berlin-Frankfurt-Münster AML Study Group

Author

Coenen , Eva A., Zwaan , C. Michel, Harrison , Christine J., Haas, Oskar A., de Haas , Valerie, Mihal, V., De Moerloose , B., Jeison, M., Rubnitz, J., Tomizawa, D., Johnston , D., Alonzo, T., Hasle, Henrik, Reinhardt , D., Auvrignon, A., Dworzak, M., Pession, A., van der Velden, V., Swansbury , J., Wong, K., Terui, K., Savasan, S., Winstanley , M., Vaitkeviciene, G., Zimmermann, M., Pieters, R., and van den Heuvel-Eibrink, M.

Published
2012

187. Detection of prognostically relevant genetic abnormalities in childhood B-cell precursor acute lymphoblastic leukaemia: recommendations from the Biology and Diagnosis Committee of iBFM-SG

Author

Harrison, Christine J, Haas, Oskar A, Harbott, W, Biondi, Andrea, Stanulla, Martin, Trka, Jan, Izraeli, Shai, Northern Institute for Cancer Research [Newcastle] (NICR), Newcastle University [Newcastle], St. Anna Children's Hospital, Department of Pediatric Hematology and Oncology, Justus-Liebig-Universität Gießen (JLU), Department of Pediatrics, Università degli Studi di Milano-Bicocca [Milano] (UNIMIB), University Medical Centre Schleswig-Holstein, Department of Paediatric Haematology/Oncology, Charles University [Prague] (CU), Leukaemia Research Centre, and The Edmund and Lily Safra Children's Hospital

Subjects
hemic and lymphatic diseases, Medicine
Abstract

International audience; Treatment of childhood acute lymphoblastic leukaemia (ALL) has improved considerably in recent years. A contributing factor has been the improved stratification for treatment according to a number of factors including genetic determinants of outcome. Here we review the current diagnostic criteria of genetic abnormalities in precursor B-ALL (BCP-ALL), including the relevant technical approaches and the application of the most appropriate methods for the detection of each abnormality. The abnormalities with the most significant impact for treatment and management of BCP-ALL are t(9;22)(q34;q11)/BCR-ABL1, t(4;11)(q21;q23)/MLL-AFF1 and near-haploidy/low hypodiploidy for high risk stratification and, to a lesser extent, t(12;21)(p13;q22)/ETV6-RUNX1 and high hyperdiploidy for good risk management. Apart from the numerical abnormalities, these can be routinely tested for by RT-PCR, providing a basic yet informative screen. However, cytogenetics, particularly fluorescence in situ hybridisation (FISH) may provide reliable alternative detection methods dependent upon the preferred technical approach within each protocol.

Published
2010

188. Clinical Impact of Additional Cytogenetic Aberrations, cKIT- and RAS Mutations and Other Factors in Pediatric t(8;21)-AML

Author

Klein, Kim, primary, Kaspers, Gertjan, additional, Harrison, Christine J., additional, Beverloo, Berna, additional, Reedijk, Ardine, additional, Bongers, Mathilda, additional, Cloos, Jacqueline, additional, Pession, Andrea, additional, Reinhardt, Dirk, additional, Zimmermann, Martin, additional, Creutzig, Ursula, additional, Dworzak, Michael, additional, Alonzo, Todd A., additional, Johnston, Donna, additional, Zapotocky, Michal, additional, Moerloose, Barbara De, additional, Fynn, Alcira, additional, Lee, Vincent, additional, Taga, Takashi, additional, Tawa, Akio, additional, Auvrignon, Anne, additional, Zeller, Bernward, additional, Salgado, Carmen, additional, Balwierz, Walentyna, additional, Popa, Alexander, additional, Rubnitz, Jeffrey E, additional, and Gibson, Brenda, additional

Published
2014
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189. EBF1-PDGFRΒ Fusion in Paediatric Acute Lymphoblastic Leukaemia (ALL): Genetic Profile and Clinical Implications

Author

Schwab, Claire, primary, Andrews, Rebecca, additional, Chilton, Lucy, additional, Elliott, Alannah, additional, Keil, Gerald, additional, Richardson, Stacey, additional, Ryan, Sarra L., additional, Wragg, Christopher, additional, Moppett, John, additional, Cummins, Michelle, additional, Goulden, Nicholas, additional, Vora, Ajay J., additional, Moorman, Anthony V., additional, and Harrison, Christine J., additional

Published
2014
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190. SSBP2-CSF1R Is a Recurrent Fusion in B-Other Acute Lymphoblastic Leukaemia with Variable Clinical Outcome

Author

Schwab, Claire, primary, Andrews, Rebecca, additional, Chilton, Lucy, additional, Elliott, Alannah, additional, Richardson, Stacey, additional, Ryan, Sarra L., additional, Logan, Amy, additional, Fielding, Adele K., additional, Goulden, Nicholas, additional, Vora, Ajay J., additional, Moorman, Anthony V., additional, Macartney, Christine A., additional, and Harrison, Christine J., additional

Published
2014
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193. Refinement of IKZF1 Genomic Status in Pediatric Philadelphia Positive Acute Lymphoblastic Leukemia

Author

Lana, Tobia, primary, de Lorenzo, Paola, additional, Bresolin, Silvia, additional, Bronzini, Ilaria, additional, Den Boer, Monique L., additional, Cave, Helene, additional, Fronkova, Eva, additional, Stanulla, Martin, additional, Zaliova, Marketa, additional, Harrison, Christine J., additional, de Groot-Kruseman, Hester, additional, Schwab, Claire, additional, Valsecchi, Maria Grazia, additional, Biondi, Andrea, additional, Basso, Giuseppe, additional, Cazzaniga, Giovanni, additional, and te Kronnie, Geertruy, additional

Published
2014
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194. The Sub-Clonal Complexity of STIL-TAL1 T-ALL

Author

Furness, Caroline L, primary, Mansur, Marcela B, additional, Weston, Victoria J, additional, Jenkinson, Sarah, additional, van Delft, Frederik W, additional, Kearney, Lyndal, additional, Titley, Ian, additional, Ford, Anthony M, additional, Gale, Rosemary E, additional, Kearns, Pamela R, additional, Ferrando, Adolfo A., additional, Harrison, Christine J., additional, Potter, Nicola E, additional, and Greaves, Mel, additional

Published
2014
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196. Diagnostic Utility of Whole Genome Sequencing in Adults with B-Other Acute Lymphoblastic Leukaemia

Author

Leongamornlert, Daniel, Gutiérrez-Abril, Jesús, Lee, SooWah, Barretta, Emilio, Creasey, Thomas, Alapi, Krisztina Zuborne, Levine, Max F., Arango-Ossa, Juan E, Medina-Martinez, Juan S, Kirkwood, Amy A., Clifton-Hadley, Laura, Patrick, Pip, Jones, David, Butler, Adam P, Harrison, Christine J., Campbell, Peter J., Patel Wrench, Bela, Moorman, Anthony V., Fielding, Adele K., and Papaemmanuil, Elli

Published
2022
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197. Treatment Outcomes of Childhood Picalm:MLLT10+ Acute Leukemias: An International Retrospective Study

Author

Mark, Catherine, Kolb, Edward A., Goemans, Bianca F., Meshinchi, Soheil, Gibson, Brenda, Bergmann, Anke K., Harrison, Christine J., Pronk, Cornelis Jan, Lapillonne, Hélène, Leverger, Guy, Antoniou, Evangelia, Attarbaschi, Andishe, Dworzak, Michael, Stary, Jan, Tomizawa, Daisuke, Lejman, Monika, Schmiegelow, Kjeld, Hasle, Henrik, Joyce, Brooklyn, Schneider, Markus, and Abla, Oussama

Published
2022
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198. Treatment Outcomes of Childhood Picalm:MLLT10+Acute Leukemias: An International Retrospective Study

Author

Mark, Catherine, Kolb, Edward A., Goemans, Bianca F., Meshinchi, Soheil, Gibson, Brenda, Bergmann, Anke K., Harrison, Christine J., Pronk, Cornelis Jan, Lapillonne, Hélène, Leverger, Guy, Antoniou, Evangelia, Attarbaschi, Andishe, Dworzak, Michael, Stary, Jan, Tomizawa, Daisuke, Lejman, Monika, Schmiegelow, Kjeld, Hasle, Henrik, Joyce, Brooklyn, Schneider, Markus, and Abla, Oussama

Published
2022
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