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

Autor: Lionel Morgado, Jean-Pierre Bourquin, Mireia Camós, Hélène Cavé, Cedric G. van der Ham, Esmé Waanders, Peter M. Hoogerbrugge, Simon V. van Reijmersdal, Roland P. Kuiper, Cornelia Eckert, Željko Antić, Ad Geurts van Kessel, Beat Bornhauser, Anthony V. Moorman, Rosemary Sutton, Giovanni Cazzaniga, Frank N. van Leeuwen, Sarah Elitzur, Edwin Sonneveld, Stefan H. Lelieveld, Jiangyan Yu
Přispěvatelé: 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, University of Zurich, Kuiper, Roland P
Jazyk: angličtina
Rok vydání: 2022
Předmět:
Oncology
medicine.medical_specialty
Lymphoblastic Leukemia
2720 Hematology
Clone (cell biology)
lnfectious Diseases and Global Health Radboud Institute for Molecular Life Sciences [Radboudumc 4]
Graft vs Host Disease
610 Medicine & health
pediatric acute lymphoblastic leukemia
clonal dynamics
Somatic evolution in cancer
very early relapse
Clonal Evolution
Recurrence
Internal medicine
medicine
Tumours of the digestive tract Radboud Institute for Molecular Life Sciences [Radboudumc 14]
Humans
2735 Pediatrics
Perinatology and Child Health
TP53
Allele
RAD21
Child
WHSC1
B cell
business.industry
Wild type
Hematology
Genomics
Precursor Cell Lymphoblastic Leukemia-Lymphoma
medicine.disease
Prognosis
Minimal residual disease
Leukemia
medicine.anatomical_structure
10036 Medical Clinic
Pediatrics
Perinatology and Child Health
2730 Oncology
business
clonal dynamic
Zdroj: PEDIATRIC BLOOD & CANCER
r-FSJD. Repositorio Institucional de Producción Científica de la Fundació Sant Joan de Déu
instname
Pediatric Blood & Cancer, 69, 1
Pediatric Blood & Cancer, 69
ISSN: 1545-5009
Popis: Contains fulltext : 248362.pdf (Publisher’s version ) (Open Access) 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.
Databáze: OpenAIRE
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