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

Lookup NU author(s): Professor Anthony Moorman

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This work is licensed under a Creative Commons Attribution-NonCommercial-NoDerivatives 4.0 International License (CC BY-NC-ND).


Abstract

© 2021 The Authors. Pediatric Blood & Cancer published by Wiley Periodicals LLCIntroduction: 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.


Publication metadata

Author(s): Antic Z, Yu J, Bornhauser BC, Lelieveld SH, van der Ham CG, van Reijmersdal SV, Morgado L, Elitzur S, Bourquin J-P, Cazzaniga G, Eckert C, Camos M, Sutton R, Cave H, Moorman AV, Sonneveld E, Geurts van Kessel A, van Leeuwen FN, Hoogerbrugge PM, Waanders E, Kuiper RP

Publication type: Article

Publication status: Published

Journal: Pediatric Blood and Cancer

Year: 2021

Issue: ePub ahead of Print

Online publication date: 01/10/2021

Acceptance date: 31/08/2021

Date deposited: 19/10/2021

ISSN (print): 1545-5009

ISSN (electronic): 1545-5017

Publisher: John Wiley and Sons Inc

URL: https://doi.org/10.1002/pbc.29361

DOI: 10.1002/pbc.29361


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