| Title: |
Clonal dynamics in pediatric B-cell precursor acute lymphoblastic leukemia with very early relapse |
| Authors: |
Antic Z.; Yu J.; Bornhauser B. C.; Lelieveld S. H.; van der Ham C. G.; van Reijmersdal S. V.; Morgado L.; Elitzur S.; Bourquin J. -P.; Cazzaniga G.; Eckert C.; Camos M.; Sutton R.; Cave H.; Moorman A. V.; Sonneveld E.; Geurts van Kessel A.; van Leeuwen F. N.; Hoogerbrugge P. M.; Waanders E.; Kuiper R. P. |
| Contributors: |
Antic, Z; Yu, J; Bornhauser, B; Lelieveld, S; van der Ham, C; van Reijmersdal, S; Morgado, L; Elitzur, S; Bourquin, J; Cazzaniga, G; Eckert, C; Camos, M; Sutton, R; Cave, H; Moorman, A; Sonneveld, E; Geurts van Kessel, A; van Leeuwen, F; Hoogerbrugge, P; Waanders, E; Kuiper, R |
| Publisher Information: |
John Wiley and Sons Inc; US |
| Publication Year: |
2022 |
| Collection: |
Università degli Studi di Milano-Bicocca: BOA (Bicocca Open Archive) |
| Subject Terms: |
clonal dynamic; pediatric acute lymphoblastic leukemia; RAD21; TP53; very early relapse; WHSC1 |
| Description: |
Introduction: One-quarter of the relapses in children with B-cell precursor acute lymphoblastic leukemia (BCP-ALL) occur very early (within 18months, 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: |
STAMPA |
| Language: |
English |
| Relation: |
info:eu-repo/semantics/altIdentifier/pmid/34597466; info:eu-repo/semantics/altIdentifier/wos/WOS:000702421700001; volume:69; issue:1; journal:PEDIATRIC BLOOD & CANCER; https://hdl.handle.net/10281/336865 |
| DOI: |
10.1002/pbc.29361 |
| Availability: |
https://hdl.handle.net/10281/336865; https://doi.org/10.1002/pbc.29361 |
| Rights: |
info:eu-repo/semantics/openAccess ; license:Creative Commons ; license uri:http://creativecommons.org/licenses/by-nc-nd/4.0/ |
| Accession Number: |
edsbas.84A6C7EC |
| Database: |
BASE |