| Title: |
Clonal dynamics in pediatric B-cell precursor acute lymphoblastic leukemia with very early relapse |
| Authors: |
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 |
| Source: |
Pediatric Blood and Cancer, 2021 |
| Publisher Information: |
John Wiley and Sons Inc |
| Publication Year: |
2021 |
| Collection: |
Newcastle University Library ePrints Service |
| Description: |
© 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. |
| Document Type: |
article in journal/newspaper |
| File Description: |
application/pdf |
| Language: |
unknown |
| Relation: |
https://eprints.ncl.ac.uk/277687; https://eprints.ncl.ac.uk/fulltext.aspx?url=277687/51FF10E1-B162-43BA-ABD7-CAB13CAA10C5.pdf&pub_id=277687 |
| Availability: |
https://eprints.ncl.ac.uk/277687 |
| Rights: |
https://creativecommons.org/licenses/by-nc-nd/4.0/ |
| Accession Number: |
edsbas.24BD69D5 |
| Database: |
BASE |