The presence of supernumerary chromosomes is the only abnormality shared by all patients diagnosed with high-hyperdiploid B cell acute lymphoblastic leukemia (HD-ALL). Despite being the most frequently diagnosed pediatric leukemia, the lack of clonal molecular lesions and complete absence of appropriate experimental models have impeded the elucidation of HD-ALL leukemogenesis. Here, we report that for 23 leukemia samples isolated from moribund Eμ-Ret mice, all were characterized by non-random chromosomal gains, involving combinations of trisomy 9, 12, 14, 15, and 17. With a median gain of three chromosomes, leukemia emerged after a prolonged latency from a preleukemic B cell precursor cell population displaying more diverse aneuploidy. Transition from preleukemia to overt disease in Eμ-Ret mice is associated with acquisition of heterogeneous genomic abnormalities affecting the expression of genes implicated in pediatric B-ALL. The development of abnormal centrosomes in parallel with aneuploidy renders both preleukemic and leukemic cells sensitive to inhibitors of centrosome clustering, enabling targeted in vivo depletion of leukemia-propagating cells. This study reveals the Eμ-Ret mouse to be a novel tool for investigating HD-ALL leukemogenesis, including supervision and selection of preleukemic aneuploid clones by the immune system and identification of vulnerabilities that could be targeted to prevent relapse.

多余染色体的存在是所有诊断为高超二倍体 B 细胞急性淋巴细胞白血病 (HD-ALL) 的患者所共有的唯一异常。尽管 HD-ALL 是最常诊断的儿童白血病，但缺乏克隆分子病变和完全缺乏适当的实验模型阻碍了 HD-ALL 白血病发生的阐明。在这里，我们报告从垂死的 Eμ-Ret 小鼠中分离出 23 个白血病样本，所有样本均具有非随机染色体增益的特征，涉及 9、12、14、15 和 17 三体性的组合。平均增益为 3 条染色体，白血病前体 B 细胞前体细胞群表现出更多样化的非整倍性，经过较长的潜伏期后出现了白血病。 Eμ-Ret 小鼠从白血病前期到明显疾病的转变与获得异质基因组异常有关，这些异常影响儿科 B-ALL 相关基因的表达。异常中心体的发育与非整倍体同时发生，使得白血病前期细胞和白血病细胞对中心体簇抑制剂敏感，从而能够在体内有针对性地消除白血病增殖细胞。这项研究表明，Eμ-Ret 小鼠是研究 HD-ALL 白血病发生的新工具，包括免疫系统对白血病前非整倍体克隆的监督和选择，以及识别可预防复发的漏洞。