1. Clonal dynamics in pediatric B-cell precursor acute lymphoblastic leukemia with very early relapse
- Author
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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, 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, and Kuiper, Roland P
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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 - Abstract
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.
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- 2022