The Eμ-Ret mouse is a novel model of hyperdiploid B-cell acute lymphoblastic leukemia. The Eμ-Ret mouse is a novel model of hyperdiploid B-cell acute lymphoblastic leukemia

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. Overall design: To identify cellular pathways involved in the transition from preleukemia to leukemia, BP-1+ B-cell precursors were harvested from 4 young, healthy Eμ-Ret mice and 3 moribund older leukemic mice. We then performed comparative gene expression profiliing of data obtained from RNA-seq of all samples

超数染色体的存在是所有确诊为高高二倍体B细胞急性淋巴细胞白血病（high-hyperdiploid B cell acute lymphoblastic leukemia, HD-ALL）的患者共有的唯一异常。尽管该疾病是最常见的儿童白血病，但由于缺乏克隆性分子病变以及合适的实验模型，HD-ALL的白血病发生机制阐释始终受阻。本研究针对23份从濒死Eμ-Ret小鼠体内分离的白血病样本展开分析，结果显示所有样本均存在非随机性染色体获得现象，涉及三体9号、12号、14号、15号和17号染色体的组合。在中位获得3条染色体的情况下，白血病于较长潜伏期后，从携带更多样非整倍性特征的白血病前期B细胞前体细胞群体中产生。Eμ-Ret小鼠体内从白血病前期进展为显性疾病的过程，与异质性基因组异常的获得密切相关，此类异常会影响儿童B细胞急性淋巴细胞白血病相关基因的表达。伴随非整倍性出现的中心体异常发育，使得白血病前期细胞与白血病细胞均对中心体聚集抑制剂敏感，由此可实现白血病增殖细胞的靶向体内清除。本研究证实，Eμ-Ret小鼠是研究HD-ALL白血病发生机制的新型工具，可用于探索免疫系统对白血病前期非整倍性克隆的监控与筛选，以及鉴定可通过靶向干预预防复发的致病脆弱位点。总体实验设计：为鉴定参与白血病前期向白血病转化的细胞通路，研究人员从4只健康年轻的Eμ-Ret小鼠以及3只濒死的老年白血病小鼠中采集了BP-1+ B细胞前体细胞，随后对所有样本的RNA测序（RNA-seq）数据开展比较基因表达谱分析。