Clonal dynamics in pediatric B-cell precursor acute lymphoblastic leukemia with very early relapse

Željko Antić, Jiangyan Yu, Beat C Bornhauser, Stefan H Lelieveld, Cedric G van der Ham, Simon V van Reijmersdal, Lionel Morgado, Sarah Elitzur, Jean-Pierre Bourquin, Giovanni Cazzaniga, Cornelia Eckert, Mireia Camós, Rosemary Sutton, Hélène Cavé, Anthony V Moorman, Edwin Sonneveld, Ad Geurts van Kessel, Frank N van Leeuwen, Peter M Hoogerbrugge, Esmé WaandersRoland P Kuiper

Research output: Contribution to journalArticle

Abstract

INTRODUCTION: One-quarter of the relapses in children with B-cell precursor acute lymphoblastic leukemia (BCP-ALL) occur very early (within 18 months, before completion of treatment), and prognosis in these patients is worse compared to cases that relapse after treatment has ended.

METHODS: In this study, we performed a genomic analysis of diagnosis-relapse pairs of 12 children who relapsed very early, followed by a deep-sequencing validation of all identified mutations. In addition, we included one case with a good initial treatment response and on-treatment relapse at the end of upfront therapy.

RESULTS: We observed a dynamic clonal evolution in all cases, with relapse almost exclusively originating from a subclone at diagnosis. We identified several driver mutations that may have influenced the outgrowth of a minor clone at diagnosis to become the major clone at relapse. For example, a minimal residual disease (MRD)-based standard-risk patient with ETV6-RUNX1-positive leukemia developed a relapse from a TP53-mutated subclone after loss of the wildtype allele. Furthermore, two patients with TCF3-PBX1-positive leukemia that developed a very early relapse carried E1099K WHSC1 mutations at diagnosis, a hotspot mutation that was recurrently encountered in other very early TCF3-PBX1-positive leukemia relapses as well. In addition to alterations in known relapse drivers, we found two cases with truncating mutations in the cohesin gene RAD21.

CONCLUSION: Comprehensive genomic characterization of diagnosis-relapse pairs shows that very early relapses in BCP-ALL frequently arise from minor subclones at diagnosis. A detailed understanding of the therapeutic pressure driving these events may aid the development of improved therapies.

Original languageEnglish
Pages (from-to)e29361
JournalPediatric blood & cancer
Volume69
Issue number1
DOIs
Publication statusPublished - 1 Jan 2022

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