TY - JOUR
T1 - Clonal dynamics in pediatric B-cell precursor acute lymphoblastic leukemia with very early relapse
AU - Antić, Željko
AU - Yu, Jiangyan
AU - Bornhauser, Beat C
AU - Lelieveld, Stefan H
AU - van der Ham, Cedric G
AU - van Reijmersdal, Simon V
AU - Morgado, Lionel
AU - Elitzur, Sarah
AU - Bourquin, Jean-Pierre
AU - Cazzaniga, Giovanni
AU - Eckert, Cornelia
AU - Camós, Mireia
AU - Sutton, Rosemary
AU - Cavé, Hélène
AU - Moorman, Anthony V
AU - Sonneveld, Edwin
AU - Geurts van Kessel, Ad
AU - van Leeuwen, Frank N
AU - Hoogerbrugge, Peter M
AU - Waanders, Esmé
AU - Kuiper, Roland P
N1 - Funding Information:
This work was supported by grants from Stichting Kinderen Kankervrij (KIKA 150 to Roland P. Kuiper), the Dutch Cancer society (KWF 12842 to Roland P. Kuiper and Frank N. van Leeuwen), and the China Scholarship Council (CSC201304910347 to Jiangyan Yu). We are grateful to MRC-Holland for their support in performing and analyzing the digital MLPA experiments. We thank Radboud University Medical Center, Department of Human Genetics for bioinformatics support in data analysis, and the Center for Biological Resources (CRB-cancer; BB-0033-00076) of the Robert Debré Hospital.
Funding Information:
This work was supported by grants from Stichting Kinderen Kankervrij (KIKA 150 to Roland P. Kuiper), the Dutch Cancer society (KWF 12842 to Roland P. Kuiper and Frank N. van Leeuwen), and the China Scholarship Council (CSC201304910347 to Jiangyan Yu). We are grateful to MRC‐Holland for their support in performing and analyzing the digital MLPA experiments. We thank Radboud University Medical Center, Department of Human Genetics for bioinformatics support in data analysis, and the Center for Biological Resources (CRB‐cancer; BB‐0033‐00076) of the Robert Debré Hospital.
Publisher Copyright:
© 2021 The Authors. Pediatric Blood & Cancer published by Wiley Periodicals LLC.
PY - 2022/1
Y1 - 2022/1
N2 - 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.
AB - 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.
KW - clonal dynamics
KW - pediatric acute lymphoblastic leukemia
KW - RAD21
KW - TP53
KW - very early relapse
KW - WHSC1
UR - http://www.scopus.com/inward/record.url?scp=85116296986&partnerID=8YFLogxK
U2 - 10.1002/pbc.29361
DO - 10.1002/pbc.29361
M3 - Article
C2 - 34597466
SN - 1545-5009
VL - 69
SP - 1
EP - 10
JO - Pediatric Blood & Cancer
JF - Pediatric Blood & Cancer
IS - 1
M1 - e29361
ER -