High hyperdiploid acute lymphoblastic leukemia (HeH ALL), one of the most common childhood malignancies, is driven by nonrandom aneuploidy (abnormal chromosome numbers) mainly comprising chromosomal gains. In this study, we investigate how aneuploidy in HeH ALL arises. Single cell whole genome sequencing of 2847 cells from nine primary cases and one normal bone marrow reveals that HeH ALL generally display low chromosomal heterogeneity, indicating that they are not characterized by chromosomal instability and showing that aneuploidy-driven malignancies are not necessarily chromosomally heterogeneous. Furthermore, most chromosomal gains are present in all leukemic cells, suggesting that they arose early during leukemogenesis. Copy number data from 577 primary cases reveals selective pressures that were used for in silico modeling of aneuploidy development. This shows that the aneuploidy in HeH ALL likely arises by an initial tripolar mitosis in a diploid cell followed by clonal evolution, in line with a punctuated evolution model.

Childhood Leukaemia Investigation Prague Prague Czech Republic

Department of Clinical Genetics Pathology and Molecular Diagnostics Office for Medical Services Region Skåne Lund Sweden

Department of Laboratory Medicine Division of Clinical Genetics Lund University Lund Sweden

Department of Pediatric Hematology and Oncology 2nd Faculty of Medicine Charles University University Hospital Motol Prague Czech Republic

Department of Pediatrics Skåne University Hospital Lund University Lund Sweden

European Research Institute for the Biology of Ageing University of Groningen University Medical Center Groningen Groningen The Netherlands

Laboratory of Hematology Centre Hospitalier Universitaire Lille Lille France

Unité Mixte de Recherche en Santé 1172 INSERM University of Lille Lille France

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Postnatal origin of the chromosomal gains in older patients with high hyperdiploid acute lymphoblastic leukemia