Constitutive Activation of RAS/MAPK Pathway Cooperates with Trisomy 21 and Is Therapeutically Exploitable in Down Syndrome B-cell Leukemia
Constitutive Activation of RAS/MAPK Pathway Cooperates with Trisomy 21 and Is Therapeutically Exploitable in Down Syndrome B-cell Leukemia
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DOI：
10.1158/1078-0432.ccr-19-3519
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发表时间：
2020-07-01
影响因子：
11.5
通讯作者：
Malinge, Sebastien
中科院分区：
文献类型：
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作者：
Laurent, Anouchka P.;Siret, Aurelie;Malinge, Sebastien
目的：与其他B细胞急性淋巴细胞白血病（B-ALL）儿童相比，患有唐氏综合征（组成性21三体）的儿童发生急性淋巴细胞白血病（DS-ALL）的治疗相关死亡率增加3倍，复发累积发生率更高。这凸显了缺乏合适的治疗唐氏综合征儿童B-ALL。实验设计：为了促进新治疗药物转化为临床试验，我们建立了第一个临床前队列的DS-ALL患者来源的异种移植（PDX）模型，在遗传和转录组水平上进行了全面表征，并已通过评估MEK抑制剂曲美替尼与常规化疗药物之间的药物组合的疗效证明其适用于临床前研究。全外显子组和RNA测序实验显示，在我们的DS-ALL队列中，以及在其他表现为21号染色体体细胞获得（B-ALL+21）的儿科B-ALL中，体细胞改变导致RAS/MAPK通路激活的发生率很高。在鼠和人B细胞前体中，激活的KRAS（G12 D）在功能上与21三体合作以解除促进增加的增殖和自我更新以及B细胞分化阻断的转录网络。此外，我们发现，使用MEK 1/2抑制剂曲美替尼抑制RAS/MAPK通路活化可降低B-ALL+21的几种PDX模型中的白血病负荷，并提高DS-ALL PDX与常规化疗药物（如长春新碱）联合治疗的生存率。总之，使用新的和合适的PDX模型，本研究表明，RAS/MAPK通路抑制是改善患有B细胞前体白血病的唐氏综合征儿童预后的一种有希望的策略。
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 KRAS(G12D) 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.