Purpose: Children with Down syndrome (constitutive trisomy 21) that develop acute lymphoblastic leukemia (DS-ALL) have a 3-fold increased likelihood of treatment-related mortality coupled with a higher cumulative incidence of relapse, compared with other children with B-cell acute lymphoblastic leukemia (B-ALL). This highlights the lack of suitable treatment for Down syndrome children with B-ALL. Experimental Design: To facilitate the translation of new therapeutic agents into clinical trials, we built the first preclinical cohort of patient-derived xenograft (PDX) models of DS-ALL, comprehensively characterized at the genetic and transcriptomic levels, and have proven its suitability for preclinical studies by assessing the efficacy of drug combination between the MEK inhibitor trametinib and conventional chemotherapy agents. Results: Whole-exome and RNA-sequencing experiments revealed a high incidence of somatic alterations leading to RAS/MAPK pathway activation in our cohort of DS-ALL, as well as in other pediatric B-ALL presenting somatic gain of the chromosome 21 (B-ALL+21). In murine and human B-cell precursors, activated KRASG12D functionally cooperates with trisomy 21 to deregulate transcriptional networks that promote increased proliferation and self renewal, as well as B-cell differentiation blockade. Moreover, we revealed that inhibition of RAS/MAPK pathway activation using the MEK1/2 inhibitor trametinib decreased leukemia burden in several PDX models of B-ALL+21, and enhanced survival of DS-ALL PDX in combination with conventional chemotherapy agents such as vincristine. Conclusions: Altogether, using novel and suitable PDX models, this study indicates that RAS/MAPK pathway inhibition represents a promising strategy to improve the outcome of Down syndrome children with B-cell precursor leukemia.

中文翻译：

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RAS/MAPK 通路的组成型激活与 21 三体协同作用，可用于治疗唐氏综合征 B 细胞白血病。

目的：发展为急性淋巴细胞白血病 (DS-ALL) 的唐氏综合征（21 三体）儿童与其他 B 细胞儿童相比，治疗相关死亡率增加 3 倍，且复发累积发生率更高。急性淋巴细胞白血病（B-ALL）。这凸显了患有 B-ALL 的唐氏综合症儿童缺乏合适的治疗方法。实验设计：为了促进新的治疗药物转化为临床试验，我们建立了 DS-ALL 患者来源的异种移植 (PDX) 模型的第一个临床前队列，在遗传和转录组水平上进行了全面表征，并证明了其适用于通过评估 MEK 抑制剂曲美替尼和常规化疗药物之间药物组合的疗效进行临床前研究。结果：全外显子组和 RNA 测序实验显示，在我们的 DS-ALL 队列以及其他呈现 21 号染色体（B-ALL）体细胞增益的儿科 B-ALL 中，导致 RAS/MAPK 通路激活的体细胞改变发生率很高+21）。在小鼠和人类 B 细胞前体中，活化的 KRASG12D 在功能上与 21 三体协同作用，解除转录网络的调节，促进增殖和自我更新，以及 B 细胞分化阻断。此外，我们发现使用 MEK1/2 抑制剂曲美替尼抑制 RAS/MAPK 通路激活可降低 B-ALL+21 的几种 PDX 模型中的白血病负担，并提高 DS-ALL PDX 与常规化疗药物（如长春新碱）联合的存活率. 结论：总而言之，使用新颖且合适的 PDX 模型，