Department of Laboratory Medicine, Division of Clinical Genetics, Lund University, Lund, Sweden.
European Research Institute for the Biology of Ageing (ERIBA), University of Groningen, University Medical Center Groningen, Groningen, The Netherlands.
Nat Commun. 2023 Mar 25;14(1):1658. doi: 10.1038/s41467-023-37356-5.
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.
高倍体超二倍体急性淋巴细胞白血病（HeH ALL）是最常见的儿童恶性肿瘤之一，主要由非随机的染色体数目异常（染色体数量异常）驱动，其中包括染色体增益。在这项研究中，我们研究了 HeH ALL 中染色体非整倍性的产生机制。对来自九个原发性病例和一个正常骨髓的 2847 个细胞进行单细胞全基因组测序，结果表明 HeH ALL 通常显示出较低的染色体异质性，这表明它们不具有染色体不稳定性的特征，并且表明非整倍体驱动的恶性肿瘤不一定具有染色体异质性。此外，大多数染色体增益都存在于所有白血病细胞中，这表明它们在白血病发生的早期就出现了。来自 577 个原发性病例的拷贝数数据揭示了选择压力，这些压力用于非整倍体发育的计算机模拟。这表明，HeH ALL 中的非整倍体可能是由二倍体细胞中的初始三极有丝分裂引起的，随后是克隆进化，与一个间断平衡模型一致。
