Diverse mutations and structural variations contribute to Notch signaling deregulation in paediatric T-cell lymphoblastic lymphoma

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Grant support

We thank the centres of the Sociedad Espanola de Hematologia y Oncologia Pediatricas that submitted cases for consultation, to Noelia Garcia, Silvia Martin and Helena Suarez for their excellent technical assistance and to Nerea Dominguez for updating clinical data. We are indebted to the IDIBAPS Genomics Core Facility and to the HCB-IDIBAPS, the HospitaI Infantil Sant Joan de Deu and the Hospital Universitari Vall d'Hebron Tumour Biobanks, all integrated in the National Network Biobanks of ISCIII for the sample and data procurement. This work was supported by Asociacion Espanola Contra el Cancer (AECC CICPFI6025SALA and 'Ayudas Clinico Formacion AECC 2020' to Jaime Verdu-Amoros), Asociacion de aitas y amas para la humanizacion, socializacion e investigacion del Cancer Infantil y la divulgacion de la donacion de medula osea-La Cuadri del Hospi, Fondo de Investigaciones Sanitarias Instituto de Salud Carlos III (Miguel Servet Program I and II CP13/00159 and MSII18/00015; Itziar Salaverria), Generalitat de Catalunya Suport Grups de Recerca (2017-SGR-1107; Itziar Salaverria), and the European Regional Development Fund 'Una manera de fer Europa'. Joan Enric Ramis-Zaldivar was supported by a fellowship AGAUR FI-DGR 2017 (2017 FI_B01004) from Generalitat de Catalunya. Noelia Garcia has been continuously supported by Accio instrumental d'incorporacio de cientifics i tecnlegs PERIS 2016 (SLT002/16/00336) and PERIS 2020 (SL017/20/000204) from Generalitat de Catalunya. Julia Salmeron-Villalobos was supported by a fellowship from La Caixa (CLLEvolution-HR17-00221). This work was developed partially at the Centro Esther Koplowitz, Barcelona, Spain.

Analysis of institutional authors

Salmeron-Villalobos JAuthorRamis-Zaldivar JeAuthorBalagué OAuthorMato SAuthorOrtega MjAuthorGonzalez-Farre BAuthorCampo EAuthorGarcia NAuthorColomer DAuthorSalaverria ICorresponding Author

August 25, 2022

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Article

Publicated to:Pediatric Blood & Cancer. 69 (11): e29926- - 2022-11-01 69(11), DOI: 10.1002/pbc.29926

Authors: Salmeron-Villalobos, Julia; Enric Ramis-Zaldivar, Joan; Balague, Olga; Verdu-Amoros, Jaime; Celis, Veronica; Sabado, Constantino; Garrido, Marta; Mato, Sara; Uriz, Javier; Ortega, M Jose; Gutierrez-Camino, Angela; Sinnett, Daniel; Illarregi, Unai; Carron, Maxime; Regueiro, Alexandra; Galera, Ana; Gonzalez-Farre, Blanca; Campo, Elias; Garcia, Noelia; Colomer, Dolors; Astigarraga, Itziar; Andres, Mara; Llavador, Margarita; Martin-Guerrero, Idoia; Salaverria, Itziar

Affiliations

Centro de Investigación Biomédica en Red-Oncología (CIBERONC), Madrid, Spain. - Author

CHU St Justine Res Ctr, Div Haematol Oncol, Montreal, PQ, Canada - Author

Ctr Invest Biomed Red Oncol CIBERONC, Madrid, Spain - Author

Donostia Univ Hosp, Biodonostia Hlth Res Inst, Paediat Oncohaematol Dept, San Sebastian, Spain - Author

Hosp Clin Barcelona, Haematopathol Unit, Barcelona, Spain - Author

Hosp Clin Univ Virgen de la Arrixaca, Paediat Oncohaematol Dept, Murcia, Spain - Author

Hosp Clin, Paediat Oncol Dept, Valencia, Spain - Author

Hosp La Fe, Anat Pathol Dept, Valencia, Spain - Author

Hosp La Fe, Paediat Oncol Dept, Valencia, Spain - Author

Hosp St Joan de Deu, Paediat Oncol Dept, Esplugas de Llobregat, Spain - Author

Hosp Univ Cruces, Biocruces Bizkaia Hlth Res Inst, Paediat Dept, Barakaldo, Baracaldo, Spain - Author

Hosp Univ Virgen de la Nieves, Paediat Oncol Dept, Granada, Spain - Author

Hosp Valle De Hebron, Anat Pathol Dept, Barcelona, Spain - Author

Hosp Valle De Hebron, Paediat Oncol Dept, Barcelona, Spain - Author

Inst Invest Biomed August Pi & Sunyer IDIBAPS, Rossello 149-153, Barcelona 08036, Spain - Author

Institut d'Investigacions Biomèdiques August Pi i Sunyer (IDIBAPS), Barcelona, Spain. - Author

Univ Basque Country, Fac Sci & Technol, Genet Phys Anthropol & Anim Physiol, Leioa, Spain - Author

Univ Basque Country, Paediat Dept, UPV EHU, Leioa, Spain - Author

Univ Basque Country, Sci & Technol Fac, Biocruces Bizkaia Hlth Res Inst, Dept Genet Phys Anthropol St Anim Physiol,UPV EHU, Leioa, Spain - Author

Univ Montreal, Fac Med, Dept Paediat, Montreal, PQ, Canada - Author

Univ Santiago de Compostela, Paediat Haematol & Oncol Dept, Hosp Clin, Santiago De Compostela, Spain - Author

Abstract

T-cell lymphoblastic lymphoma (T-LBL) is an aggressive neoplasm closely related to T-cell acute lymphoblastic leukaemia (T-ALL). Despite their similarities, and contrary to T-ALL, studies on paediatric T-LBL are scarce and, therefore, its molecular landscape has not yet been fully elucidated. Thus, the aims of this study were to characterize the genetic and molecular heterogeneity of paediatric T-LBL and to evaluate novel molecular markers differentiating this entity from T-ALL.Thirty-three paediatric T-LBL patients were analyzed using an integrated approach, including targeted next-generation sequencing, RNA-sequencing transcriptome analysis and copy-number arrays.Copy number and mutational analyses allowed the detection of recurrent homozygous deletions of 9p/CDKN2A (78%), trisomy 20 (19%) and gains of 17q24-q25 (16%), as well as frequent mutations of NOTCH1 (62%), followed by the BCL11B (23%), WT1 (19%) and FBXW7, PHF6 and RPL10 genes (15%, respectively). This genetic profile did not differ from that described in T-ALL in terms of mutation incidence and global genomic complexity level, but unveiled virtually exclusive 17q25 gains and trisomy 20 in T-LBL. Additionally, we identified novel gene fusions in paediatric T-LBL, including NOTCH1-IKZF2, RNGTT-SNAP91 and DDX3X-MLLT10, the last being the only one previously described in T-ALL. Moreover, clinical correlations highlighted the presence of Notch pathway alterations as a factor related to favourable outcome.In summary, the genomic landscape of paediatric T-LBL is similar to that observed in T-ALL, and Notch signaling pathway deregulation remains the cornerstone in its pathogenesis, including not only mutations but fusion genes targeting NOTCH1.© 2022 The Authors. Pediatric Blood & Cancer published by Wiley Periodicals LLC.

Keywords

adolescentscancerchildhoodchildrenchromosome-abnormalitiesexpressionnotchpaediatricproteinstratificationt-cell lymphoblastic lymphomat-lbltumor-suppressor geneAcute myeloid-leukemiaChildChromosomes, human, pair 20F-box-wd repeat-containing protein 7HumansLymphoma, t-cellMolecular geneticsMosaicismMutationNotchPaediatricPrecursor t-cell lymphoblastic leukemia-lymphomaReceptor, notch1RnaSignal transductionT-cell lymphoblastic lymphomaT-lblT-lymphocytesTranscription factorsTrisomyTumor suppressor proteins

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Bibliometric impact. Analysis of the contribution and dissemination channel

The work has been published in the journal Pediatric Blood & Cancer due to its progression and the good impact it has achieved in recent years, according to the agency Scopus (SJR), it has become a reference in its field. In the year of publication of the work, 2022, it was in position , thus managing to position itself as a Q1 (Primer Cuartil), in the category Pediatrics, Perinatology and Child Health.

From a relative perspective, and based on the normalized impact indicator calculated from the Field Citation Ratio (FCR) of the Dimensions source, it yields a value of: 4.33, which indicates that, compared to works in the same discipline and in the same year of publication, it ranks as a work cited above average. (source consulted: Dimensions Jul 2025)

Specifically, and according to different indexing agencies, this work has accumulated citations as of 2025-07-20, the following number of citations:

WoS: 7
Scopus: 8
Europe PMC: 1

Impact and social visibility

Leadership analysis of institutional authors

This work has been carried out with international collaboration, specifically with researchers from: Canada; Granada.

There is a significant leadership presence as some of the institution’s authors appear as the first or last signer, detailed as follows: First Author (Salmeron Villalobos, Julia) and Last Author (Salaverria Frigola, Itziar).