Clonal heterogeneity and rates of specific chromosome gains are risk predictors in childhood high-hyperdiploid B-cell acute lymphoblastic leukemia

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• dc.contributor.author Ramos-Muntada, Mireia
• dc.contributor.author Trincado Alonso, Juan Luis, 1987-
• dc.contributor.author Molina, Oscar
• dc.date.accessioned 2022-11-03T07:10:35Z
• dc.date.available 2022-11-03T07:10:35Z
• dc.date.issued 2022
• dc.description.abstract B-cell acute lymphoblastic leukemia (B-ALL) is the commonest childhood cancer. High hyperdiploidy (HHD) identifies the most frequent cytogenetic subgroup in childhood B-ALL. Although hyperdiploidy represents an important prognostic factor in childhood B-ALL, the specific chromosome gains with prognostic value in HHD-B-ALL remain controversial, and the current knowledge about the hierarchy of chromosome gains, clonal heterogeneity and chromosomal instability in HHD-B-ALL remains very limited. We applied automated sequential-iFISH coupled with single-cell computational modeling to identify the specific chromosomal gains of the eight typically gained chromosomes in a large cohort of 72 primary diagnostic (DX, n = 62) and matched relapse (REL, n = 10) samples from HHD-B-ALL patients with either favorable or unfavorable clinical outcome in order to characterize the clonal heterogeneity, specific chromosome gains and clonal evolution. Our data show a high degree of clonal heterogeneity and a hierarchical order of chromosome gains in DX samples of HHD-B-ALL. The rates of specific chromosome gains and clonal heterogeneity found in DX samples differ between HHD-B-ALL patients with favorable or unfavorable clinical outcome. In fact, our comprehensive analyses at DX using a computationally defined risk predictor revealed low levels of trisomies +18+10 and low levels of clonal heterogeneity as robust relapse risk factors in minimal residual disease (MRD)-negative childhood HHD-B-ALL patients: relapse-free survival beyond 5 years: 22.1% versus 87.9%, P < 0.0001 and 33.3% versus 80%, P < 0.0001, respectively. Moreover, longitudinal analysis of matched DX-REL HHD-B-ALL samples revealed distinct patterns of clonal evolution at relapse. Our study offers a reliable prognostic sub-stratification of pediatric MRD-negative HHD-B-ALL patients.
• dc.description.sponsorship This work is supported by the Spanish Ministry of Science and Innovation (PID2019-108160RB-I00/AEI/10.13039/501100011033, the European Research Council (CoG-2014-646903), the Spanish Ministry of Economy and Competitiveness (SAF2016-80481-R and SAF-2019-108160-R), the Leo Messi Foundation, the Health Institute Carlos III (ISCIII) (RICORS, RD21/0017/0029) within the Next Generation EU program (plan de recuperación, transformación y resilencia), and the Fundación Uno entre Cienmil (PM). Additional funding was provided by the ISCIII (FEDER PI17/01028 and PI20/00822) (CB), the Generalitat de Catalunya (2017/SGR-503) and the Universitat Autònoma de Barcelona (UAB/CF-180034) (JB) and the Blood Cancer UK (CJH). JLT was supported by a Juan de la Cierva fellowship by the Spanish Ministry of Science and Innovation (FJC2019-040868-I), BL-M was supported by the Asociación Española Contra el Cáncer (AECC; INVES20011LÓPE). AB was supported by the Fundación Española de Hematología y Hemoterapia (FEHH). OM was supported by a Beatriu de Pinós Postdoctoral Fellowship (BP2016-00048) from AGAUR (Generalitat de Catalunya), a 2017 Lady Tata Memorial Trust International Award, and the AECC (INVES211226MOLI). PM is an investigator of the Spanish Cell Therapy cooperative network (TERCEL).
• dc.format.mimetype application/pdf
• dc.identifier.citation Ramos-Muntada M, Trincado JL, Blanco J, Bueno C, Rodríguez-Cortez VC, Bataller A et al. Clonal heterogeneity and rates of specific chromosome gains are risk predictors in childhood high-hyperdiploid B-cell acute lymphoblastic leukemia. Mol Oncol. 2022 Aug;16(16):2899-919. DOI: 10.1002/1878-0261.13276
• dc.identifier.doi http://dx.doi.org/10.1002/1878-0261.13276
• dc.identifier.issn 1574-7891
• dc.identifier.uri http://hdl.handle.net/10230/54666
• dc.language.iso eng
• dc.publisher Wiley
• dc.relation.ispartof Mol Oncol. 2022 Aug;16(16):2899-919
• dc.relation.projectID info:eu-repo/grantAgreement/ES/2PE/PID2019-108160RB-I00
• dc.relation.projectID info:eu-repo/grantAgreement/ES/2PE/FJC2019-040868-I
• dc.relation.projectID info:eu-repo/grantAgreement/ES/2PE/SAF-2019-108160-R
• dc.relation.projectID info:eu-repo/grantAgreement/ES/1PE/SAF2016-80481-R
• dc.rights © 2022 The Authors. Molecular Oncology published by John Wiley & Sons Ltd on behalf of Federation of European Biochemical Societies. This is an open access article under the terms of the Creative Commons Attribution License, which permits use, distribution and reproduction in any medium, provided the original work is properly cited.
• dc.rights.accessRights info:eu-repo/semantics/openAccess
• dc.rights.uri http://creativecommons.org/licenses/by/4.0/
• dc.subject.keyword Chromosomal gains
• dc.subject.keyword Clonal heterogeneity
• dc.subject.keyword Computational modeling
• dc.subject.keyword High-hyperdiploid B-ALL
• dc.subject.keyword Risk predictors
• dc.subject.keyword Sequential iFISH
• dc.title Clonal heterogeneity and rates of specific chromosome gains are risk predictors in childhood high-hyperdiploid B-cell acute lymphoblastic leukemia
• dc.type info:eu-repo/semantics/article
• dc.type.version info:eu-repo/semantics/publishedVersion