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

Mireia Ramos-Muntada, Juan L. Trincado, Joan Blanco, Clara Bueno, Virginia C. Rodríguez-Cortez, Alex Bataller, Belén López-Millán, Claire Schwab, Margarita Ortega, Pablo Velasco, Maria L. Blanco, Josep Nomdedeu, Manuel Ramírez-Orellana, Alfredo Minguela, Jose L. Fuster, Esther Cuatrecasas, Mireia Camós, Paola Ballerini, Gabriele Escherich, Judith BoerMonique DenBoer, Jesús M. Hernández-Rivas, Maria J. Calasanz, Giovanni Cazzaniga, Christine J. Harrison, Pablo Menéndez*, Oscar Molina*

*Corresponding author for this work

Research output: Contribution to journalArticleAcademicpeer-review

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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.

Original languageEnglish
Pages (from-to)2899-2919
Number of pages21
JournalMolecular Oncology
Volume16
Issue number16
Early online date21 Jun 2022
DOIs
Publication statusPublished - Aug 2022

Bibliographical note

Funding Information:
The authors thank Anthony V Moorman (University of Newcastle, UK) and Francesc Solé (Josep Carreras Leukemia Research Institute) for critical discussions. Special thanks to Francisco Gutierrez-Agüera, Paola Romecín and Talía Velasco-Hernández (PM's lab) for technical help. We thank the CERCA program (Generalitat de Catalunya) and the Josep Carreras Foundation-Obra Social la Caixa for institutional support. 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).

Funding Information:
The authors thank Anthony V Moorman (University of Newcastle, UK) and Francesc Solé (Josep Carreras Leukemia Research Institute) for critical discussions. Special thanks to Francisco Gutierrez‐Agüera, Paola Romecín and Talía Velasco‐Hernández (PM's lab) for technical help. We thank the CERCA program (Generalitat de Catalunya) and the Josep Carreras Foundation‐Obra Social la Caixa for institutional support. 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).

Publisher Copyright:
© 2022 The Authors. Molecular Oncology published by John Wiley & Sons Ltd on behalf of Federation of European Biochemical Societies.

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