CCND2 and CCND3 hijack immunoglobulin light chain enhancers in cyclin D1-negative mantle cell lymphoma

Martín García, David; Navarro López, Alba; Valdés Mas, Rafael; Clot Razquin, Guillem; Gutiérrez-Abril, Jesús; Prieto, Miriam; Ribera Cortada, Inmaculada; Woroniecka, Renata; Rymkiewicz, Grzegorz; Bens, Susanne; Leval, Laurence de; Rosenwald, Andreas; Ferry, Judith A.; Hsi, Eric D.; Fu, Kai; Delabie, Jan; Weisenburger, Dennis D.; Jong, Daphne de; Climent, Fina; O'Connor, Sheila J.; Swerdlow, Steven H.; Torrents Arenales, David; Beltran i Agulló, Sergi; Espinet Solà, Blanca; González Farré, Blanca; Veloza, Luis; Costa, Dolors; Matutes, Estella; Siebert, Reiner; Ott, German; Quintanilla Martinez, Leticia; Jaffe, Elaine S.; López-Otin, Carlos; Salaverria Frigola, Itziar; Puente, Xose S.; Campo Güerri, Elias; Beà Bobet, Sílvia M.

CCND2 and CCND3 hijack immunoglobulin light chain enhancers in cyclin D1-negative mantle cell lymphoma

Mantle cell lymphoma (MCL) is characterized by the t(11;14)(q13;q32) translocation resulting in overexpression of cyclin D1. However, a small subset of cyclin D1− MCL has been recognized, and approximately one-half of them harbor CCND2 translocations while the primary event in cyclin D1−/D2− MCL rem...

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Authors:	Martín García, David, Navarro López, Alba, Valdés Mas, Rafael, Clot Razquin, Guillem, Gutiérrez-Abril, Jesús, Prieto, Miriam, Ribera Cortada, Inmaculada, Woroniecka, Renata, Rymkiewicz, Grzegorz, Bens, Susanne, Leval, Laurence de, Rosenwald, Andreas, Ferry, Judith A., Hsi, Eric D., Fu, Kai, Delabie, Jan, Weisenburger, Dennis D., Jong, Daphne de, Climent, Fina, O'Connor, Sheila J., Swerdlow, Steven H., Torrents Arenales, David, Beltran i Agulló, Sergi, Espinet Solà, Blanca, González Farré, Blanca, Veloza, Luis, Costa, Dolors, Matutes, Estella, Siebert, Reiner, Ott, German, Quintanilla Martinez, Leticia, Jaffe, Elaine S., López-Otin, Carlos, Salaverria Frigola, Itziar, Puente, Xose S., Campo Güerri, Elias, Beà Bobet, Sílvia M.
Format:	article
Status:	Versión aceptada para publicación
Publication Date:	2019
Country:	España
Institution:	Varias* (Consorci de Biblioteques Universitáries de Catalunya, Centre de Serveis Científics i Acadèmics de Catalunya)
Repository:	Recercat. Dipósit de la Recerca de Catalunya
OAI Identifier:	oai:recercat.cat:2445/147397
Online Access:	https://hdl.handle.net/2445/147397
Access Level:	Open access
Keyword:	Limfomes Carcinogènesi Pronòstic mèdic Lymphomas Carcinogenesis Prognosis

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spelling	CCND2 and CCND3 hijack immunoglobulin light chain enhancers in cyclin D1-negative mantle cell lymphomaMartín García, DavidNavarro López, AlbaValdés Mas, RafaelClot Razquin, GuillemGutiérrez-Abril, JesúsPrieto, MiriamRibera Cortada, InmaculadaWoroniecka, RenataRymkiewicz, GrzegorzBens, SusanneLeval, Laurence deRosenwald, AndreasFerry, Judith A.Hsi, Eric D.Fu, KaiDelabie, JanWeisenburger, Dennis D.Jong, Daphne deCliment, FinaO'Connor, Sheila J.Swerdlow, Steven H.Torrents Arenales, DavidBeltran i Agulló, SergiEspinet Solà, BlancaGonzález Farré, BlancaVeloza, LuisCosta, DolorsMatutes, EstellaSiebert, ReinerOtt, GermanQuintanilla Martinez, LeticiaJaffe, Elaine S.López-Otin, CarlosSalaverria Frigola, ItziarPuente, Xose S.Campo Güerri, EliasBeà Bobet, Sílvia M.LimfomesCarcinogènesiPronòstic mèdicLymphomasCarcinogenesisPrognosisMantle cell lymphoma (MCL) is characterized by the t(11;14)(q13;q32) translocation resulting in overexpression of cyclin D1. However, a small subset of cyclin D1− MCL has been recognized, and approximately one-half of them harbor CCND2 translocations while the primary event in cyclin D1−/D2− MCL remains elusive. To identify other potential mechanisms driving MCL pathogenesis, we investigated 56 cyclin D1−/SOX11+ MCL by fluorescence in situ hybridization (FISH), whole-genome/exome sequencing, and gene-expression and copy-number arrays. FISH with break-apart probes identified CCND2 rearrangements in 39 cases (70%) but not CCND3 rearrangements. We analyzed 3 of these negative cases by whole-genome/exome sequencing and identified IGK (n = 2) and IGL (n = 1) enhancer hijackings near CCND3 that were associated with cyclin D3 overexpression. By specific FISH probes, including the IGK enhancer region, we detected 10 additional cryptic IGK juxtapositions to CCND3 (6 cases) and CCND2 (4 cases) in MCL that overexpressed, respectively, these cyclins. A minor subset of 4 cyclin D1− MCL cases lacked cyclin D rearrangements and showed upregulation of CCNE1 and CCNE2. These cases had blastoid morphology, high genomic complexity, and CDKN2A and RB1 deletions. Both genomic and gene-expression profiles of cyclin D1− MCL cases were indistinguishable from cyclin D1+ MCL. In conclusion, virtually all cyclin D1− MCLs carry CCND2/CCND3 rearrangements with immunoglobulin genes, including a novel IGK/L enhancer hijacking mechanism. A subset of cyclin D1−/D2−/D3− MCL with aggressive features has cyclin E dysregulation. Specific FISH probes may allow the molecular identification and diagnosis of cyclin D1− MCL.American Society of Hematology2020202020192020info:eu-repo/semantics/articleinfo:eu-repo/semantics/acceptedVersion30 p.application/pdfhttps://hdl.handle.net/2445/147397Articles publicats en revistes (Fonaments Clínics)reponame:Recercat. Dipósit de la Recerca de Catalunyainstname:Varias* (Consorci de Biblioteques Universitáries de Catalunya, Centre de Serveis Científics i Acadèmics de Catalunya)InglésVersió postprint del document publicat a: https://doi.org/10.1182/blood-2018-07-862151Blood, 2019, vol. 133, num. 9, p. 940-951https://doi.org/10.1182/blood-2018-07-862151(c) American Society of Hematology, 2018info:eu-repo/semantics/openAccessoai:recercat.cat:2445/1473972026-05-29T05:05:01Z
dc.title.none.fl_str_mv	CCND2 and CCND3 hijack immunoglobulin light chain enhancers in cyclin D1-negative mantle cell lymphoma
title	CCND2 and CCND3 hijack immunoglobulin light chain enhancers in cyclin D1-negative mantle cell lymphoma
spellingShingle	CCND2 and CCND3 hijack immunoglobulin light chain enhancers in cyclin D1-negative mantle cell lymphoma Martín García, David Limfomes Carcinogènesi Pronòstic mèdic Lymphomas Carcinogenesis Prognosis
title_short	CCND2 and CCND3 hijack immunoglobulin light chain enhancers in cyclin D1-negative mantle cell lymphoma
title_full	CCND2 and CCND3 hijack immunoglobulin light chain enhancers in cyclin D1-negative mantle cell lymphoma
title_fullStr	CCND2 and CCND3 hijack immunoglobulin light chain enhancers in cyclin D1-negative mantle cell lymphoma
title_full_unstemmed	CCND2 and CCND3 hijack immunoglobulin light chain enhancers in cyclin D1-negative mantle cell lymphoma
title_sort	CCND2 and CCND3 hijack immunoglobulin light chain enhancers in cyclin D1-negative mantle cell lymphoma
dc.creator.none.fl_str_mv	Martín García, David Navarro López, Alba Valdés Mas, Rafael Clot Razquin, Guillem Gutiérrez-Abril, Jesús Prieto, Miriam Ribera Cortada, Inmaculada Woroniecka, Renata Rymkiewicz, Grzegorz Bens, Susanne Leval, Laurence de Rosenwald, Andreas Ferry, Judith A. Hsi, Eric D. Fu, Kai Delabie, Jan Weisenburger, Dennis D. Jong, Daphne de Climent, Fina O'Connor, Sheila J. Swerdlow, Steven H. Torrents Arenales, David Beltran i Agulló, Sergi Espinet Solà, Blanca González Farré, Blanca Veloza, Luis Costa, Dolors Matutes, Estella Siebert, Reiner Ott, German Quintanilla Martinez, Leticia Jaffe, Elaine S. López-Otin, Carlos Salaverria Frigola, Itziar Puente, Xose S. Campo Güerri, Elias Beà Bobet, Sílvia M.
author	Martín García, David
author_facet	Martín García, David Navarro López, Alba Valdés Mas, Rafael Clot Razquin, Guillem Gutiérrez-Abril, Jesús Prieto, Miriam Ribera Cortada, Inmaculada Woroniecka, Renata Rymkiewicz, Grzegorz Bens, Susanne Leval, Laurence de Rosenwald, Andreas Ferry, Judith A. Hsi, Eric D. Fu, Kai Delabie, Jan Weisenburger, Dennis D. Jong, Daphne de Climent, Fina O'Connor, Sheila J. Swerdlow, Steven H. Torrents Arenales, David Beltran i Agulló, Sergi Espinet Solà, Blanca González Farré, Blanca Veloza, Luis Costa, Dolors Matutes, Estella Siebert, Reiner Ott, German Quintanilla Martinez, Leticia Jaffe, Elaine S. López-Otin, Carlos Salaverria Frigola, Itziar Puente, Xose S. Campo Güerri, Elias Beà Bobet, Sílvia M.
author_role	author
author2	Navarro López, Alba Valdés Mas, Rafael Clot Razquin, Guillem Gutiérrez-Abril, Jesús Prieto, Miriam Ribera Cortada, Inmaculada Woroniecka, Renata Rymkiewicz, Grzegorz Bens, Susanne Leval, Laurence de Rosenwald, Andreas Ferry, Judith A. Hsi, Eric D. Fu, Kai Delabie, Jan Weisenburger, Dennis D. Jong, Daphne de Climent, Fina O'Connor, Sheila J. Swerdlow, Steven H. Torrents Arenales, David Beltran i Agulló, Sergi Espinet Solà, Blanca González Farré, Blanca Veloza, Luis Costa, Dolors Matutes, Estella Siebert, Reiner Ott, German Quintanilla Martinez, Leticia Jaffe, Elaine S. López-Otin, Carlos Salaverria Frigola, Itziar Puente, Xose S. Campo Güerri, Elias Beà Bobet, Sílvia M.
author2_role	author author author author author author author author author author author author author author author author author author author author author author author author author author author author author author author author author author author author
dc.subject.none.fl_str_mv	Limfomes Carcinogènesi Pronòstic mèdic Lymphomas Carcinogenesis Prognosis
topic	Limfomes Carcinogènesi Pronòstic mèdic Lymphomas Carcinogenesis Prognosis
description	Mantle cell lymphoma (MCL) is characterized by the t(11;14)(q13;q32) translocation resulting in overexpression of cyclin D1. However, a small subset of cyclin D1− MCL has been recognized, and approximately one-half of them harbor CCND2 translocations while the primary event in cyclin D1−/D2− MCL remains elusive. To identify other potential mechanisms driving MCL pathogenesis, we investigated 56 cyclin D1−/SOX11+ MCL by fluorescence in situ hybridization (FISH), whole-genome/exome sequencing, and gene-expression and copy-number arrays. FISH with break-apart probes identified CCND2 rearrangements in 39 cases (70%) but not CCND3 rearrangements. We analyzed 3 of these negative cases by whole-genome/exome sequencing and identified IGK (n = 2) and IGL (n = 1) enhancer hijackings near CCND3 that were associated with cyclin D3 overexpression. By specific FISH probes, including the IGK enhancer region, we detected 10 additional cryptic IGK juxtapositions to CCND3 (6 cases) and CCND2 (4 cases) in MCL that overexpressed, respectively, these cyclins. A minor subset of 4 cyclin D1− MCL cases lacked cyclin D rearrangements and showed upregulation of CCNE1 and CCNE2. These cases had blastoid morphology, high genomic complexity, and CDKN2A and RB1 deletions. Both genomic and gene-expression profiles of cyclin D1− MCL cases were indistinguishable from cyclin D1+ MCL. In conclusion, virtually all cyclin D1− MCLs carry CCND2/CCND3 rearrangements with immunoglobulin genes, including a novel IGK/L enhancer hijacking mechanism. A subset of cyclin D1−/D2−/D3− MCL with aggressive features has cyclin E dysregulation. Specific FISH probes may allow the molecular identification and diagnosis of cyclin D1− MCL.
publishDate	2019
dc.date.none.fl_str_mv	2019 2020 2020 2020
dc.type.none.fl_str_mv	info:eu-repo/semantics/article info:eu-repo/semantics/acceptedVersion
format	article
status_str	acceptedVersion
dc.identifier.none.fl_str_mv	https://hdl.handle.net/2445/147397
url	https://hdl.handle.net/2445/147397
dc.language.none.fl_str_mv	Inglés
language_invalid_str_mv	Inglés
dc.relation.none.fl_str_mv	Versió postprint del document publicat a: https://doi.org/10.1182/blood-2018-07-862151 Blood, 2019, vol. 133, num. 9, p. 940-951 https://doi.org/10.1182/blood-2018-07-862151
dc.rights.none.fl_str_mv	(c) American Society of Hematology, 2018 info:eu-repo/semantics/openAccess
rights_invalid_str_mv	(c) American Society of Hematology, 2018
eu_rights_str_mv	openAccess
dc.format.none.fl_str_mv	30 p. application/pdf
dc.publisher.none.fl_str_mv	American Society of Hematology
publisher.none.fl_str_mv	American Society of Hematology
dc.source.none.fl_str_mv	Articles publicats en revistes (Fonaments Clínics) reponame:Recercat. Dipósit de la Recerca de Catalunya instname:Varias* (Consorci de Biblioteques Universitáries de Catalunya, Centre de Serveis Científics i Acadèmics de Catalunya)
instname_str	Varias* (Consorci de Biblioteques Universitáries de Catalunya, Centre de Serveis Científics i Acadèmics de Catalunya)
reponame_str	Recercat. Dipósit de la Recerca de Catalunya
collection	Recercat. Dipósit de la Recerca de Catalunya
repository.name.fl_str_mv
repository.mail.fl_str_mv
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score	15,812429

CCND2 and CCND3 hijack immunoglobulin light chain enhancers in cyclin D1-negative mantle cell lymphoma

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