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Unraveling the cellular origin and clinical prognostic markers of infant B-cell acute lymphoblastic leukemia using genome-wide analysis

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dc.contributor.author Agraz-Doblas, Antonio
dc.contributor.author Bueno, Clara
dc.contributor.author Bashford-Rogers, Rachael
dc.contributor.author Roy, Anindita
dc.contributor.author Schneider, Pauline
dc.contributor.author Bardini, Michela
dc.contributor.author Ballerini, Paola
dc.contributor.author Cazzaniga, Gianni
dc.contributor.author Moreno, Thaidy
dc.contributor.author Revilla, Carlos
dc.contributor.author Gut, Marta
dc.contributor.author Valsecchi, Maria G.
dc.contributor.author Roberts, Irene
dc.contributor.author Pieters, Rob
dc.contributor.author De Lorenzo, Paola
dc.contributor.author Varela, Ignacio
dc.contributor.author Menéndez, Pablo
dc.contributor.author Stam, Ronald W.
dc.date.accessioned 2019-07-30T07:42:28Z
dc.date.available 2019-07-30T07:42:28Z
dc.date.issued 2019
dc.identifier.citation Agraz-Doblas A, Bueno C, Bashford-Rogers R, Roy A, Schneider P, Bardini M et al. Unraveling the cellular origin and clinical prognostic markers of infant B-cell acute lymphoblastic leukemia using genome-wide analysis. Haematologica. 2019 Jun;104(6):1176-88. DOI: 10.3324/haematol.2018.206375
dc.identifier.issn 0390-6078
dc.identifier.uri http://hdl.handle.net/10230/42199
dc.description.abstract B-cell acute lymphoblastic leukemia is the commonest childhood cancer. In infants, B-cell acute lymphoblastic leukemia remains fatal, especially in patients with t(4;11), present in ~80% of cases. The pathogenesis of t(4;11)/KMT2A-AFF1+ (MLL-AF4+) infant B-cell acute lymphoblastic leukemia remains difficult to model, and the pathogenic contribution in cancer of the reciprocal fusions resulting from derivative translocated-chromosomes remains obscure. Here, "multi-layered" genome-wide analyses and validation were performed on a total of 124 de novo cases of infant B-cell acute lymphoblastic leukemia uniformly diagnosed and treated according to the Interfant 99/06 protocol. These patients showed the most silent mutational landscape reported so far for any sequenced pediatric cancer. Recurrent mutations were exclusively found in K-RAS and N-RAS, were subclonal and were frequently lost at relapse, despite a larger number of non-recurrent/non-silent mutations. Unlike non-MLL-rearranged B-cell acute lymphoblastic leukemias, B-cell receptor repertoire analysis revealed minor, non-expanded B-cell clones in t(4;11)+ infant B-cell acute lymphoblastic leukemia, and RNA-sequencing showed transcriptomic similarities between t(4;11)+ infant B-cell acute lymphoblastic leukemias and the most immature human fetal liver hematopoietic stem and progenitor cells, confirming a "pre-VDJ" fetal cellular origin for both t(4;11) and RAS mut The reciprocal fusion AF4-MLL was expressed in only 45% (19/43) of the t(4;11)+ patients, and HOXA cluster genes are exclusively expressed in AF4-MLL-expressing patients. Importantly, AF4-MLL/HOXA-expressing patients had a significantly better 4-year event-free survival (62.4% vs 11.7%, P=0.001), and overall survival (73.7 vs 25.2%, P=0.016). AF4-MLL expression retained its prognostic significance when analyzed in a Cox model adjusting for risk stratification according to the Interfant-06 protocol based on age at diagnosis, white blood cell count and response to prednisone. This study has clinical implications for disease outcome and diagnostic risk-stratification of t(4;11)+ infant B-cell acute lymphoblastic leukemia.
dc.description.sponsorship The human fetal material was provided by the Joint MRC/Wellcome Trust (grant# MR/R006237/1) Human Developmental Biology Resource (http://hdbr.org). This work was supported by the European Research Council (CoG-2014-646903 to PM; and StG-2014-637904 to IV), the Spanish Ministry of Economy and Competitiveness (SAF-SAF2013-43065 to PM and SAF2016-76758-R to IV), the Asociación Española Contra el Cáncer (AECC-CI-2015), FERO Foundation, and the ISCIII (PI14-01191) to CB. PM/IV also acknowledge financial support from The Obra Social La Caixa-Fundaciò Josep Carreras, The Inocente Inocente Foundation, Fundación Ramón Areces and The Generalitat de Catalunya (SGR330). IR was supported by a Programme Grant from Bloodwise (LLR 13001). PM is an investigator of the Spanish Cell Therapy cooperative network (TERCEL). AR was supported by a Clinician Scientist Fellowship from Bloodwise (14041)
dc.format.mimetype application/pdf
dc.language.iso eng
dc.publisher Ferrata Storti Foundation
dc.relation.ispartof Haematologica. 2019 Jun;104(6):1176-88
dc.rights © 2019 Ferrata Storti Foundation. Material published in Haematologica is covered by copyright. All rights are reserved to the Ferrata Storti Foundation. This published material is allowed under the following terms and conditions: http://creativecommons.org/licenses/by-nc/4.0/legalcode
dc.rights.uri http://creativecommons.org/licenses/by-nc/4.0/
dc.subject.other Leucèmia
dc.subject.other Genètica
dc.subject.other Genòmica
dc.subject.other Infants
dc.title Unraveling the cellular origin and clinical prognostic markers of infant B-cell acute lymphoblastic leukemia using genome-wide analysis
dc.type info:eu-repo/semantics/article
dc.identifier.doi http://dx.doi.org/10.3324/haematol.2018.206375
dc.relation.projectID info:eu-repo/grantAgreement/EC/H2020/646903
dc.relation.projectID info:eu-repo/grantAgreement/EC/H2020/637904
dc.relation.projectID info:eu-repo/grantAgreement/ES/1PE/SAF2013-43065
dc.relation.projectID info:eu-repo/grantAgreement/ES/1PE/SAF2016-76758-R
dc.rights.accessRights info:eu-repo/semantics/openAccess
dc.type.version info:eu-repo/semantics/publishedVersion

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