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. 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被诊断为高超二倍体B细胞急性淋巴细胞白血病（high-hyperdiploid B cell acute lymphoblastic leukemia, HD-ALL）患者共有的唯一异常。尽管该疾病是临床最常见的儿童白血病类型，但由于缺乏克隆性分子病变且尚无合适的实验模型，极大阻碍了HD-ALL白血病发生机制的阐明。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，所有样本均表现出非随机性染色体拷贝数增加，涉及9、12、14、15及17号染色体三体的组合。小鼠平均获得3条异常染色体，白血病发生于一段较长的潜伏期后，其起源为一类呈现更多样化非整倍性的白血病前期B细胞前体细胞群。在Eμ-Ret小鼠中，从白血病前期进展为显性疾病的过程，伴随获得了异质性基因组异常，这些异常可调控与儿童B细胞急性淋巴细胞白血病相关的基因表达。伴随非整倍性出现的异常中心体发育，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，这为靶向体内清除白血病增殖细胞提供了可行策略。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，可用于探究免疫系统对白血病前期非整倍体克隆的监控与筛选过程，以及鉴定可作为治疗靶点以预防复发的细胞脆弱性。为明确白血病前期向白血病转化过程中涉及的细胞通路，本研究从4只年轻健康的Eμ-Ret小鼠与3只濒死的老年白血病小鼠体内分离获取了BP-1阳性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。