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Relapse fated latent diagnosis subclones in acute B lineage leukaemia are drug tolerant and possess distinct metabolic programs.

急性 B 谱系白血病的复发潜伏诊断亚克隆是药物耐受的,具有不同的代谢程序。

  • 影响因子:6.22
  • DOI:10.1158/2159-8290.CD-19-1059
  • 作者列表:"Dobson SM","Garcia-Prat L","Vanner RJ","Wintersinger J","Waanders E","Gu Z","McLeod J","Gan OI","Grandal I","Payne-Turner D","Edmonson MN","Ma X","Fan Y","Voisin V","Chan-Seng-Yue M","Xie SZ","Hosseini M","Abelson S","Gupta P","Rusch M","Shao Y","Olsen SR","Neale G","Chan SM","Bader G","Easton J","Guidos CJ","Danska JS","Zhang J","Minden MD","Morris Q","Mullighan CG","Dick JE
  • 发表时间:2020-02-21
Abstract

:Disease recurrence causes significant mortality in B-progenitor acute lymphoblastic leukemia (B-ALL). Genomic analysis of matched diagnosis and relapse samples show relapse often arising from minor diagnosis subclones. However, why therapy eradicates some subclones while others survive and progress to relapse remains obscure. Elucidation of mechanisms underlying these differing fates requires functional analysis of isolated subclones. Here, large-scale limiting dilution xenografting of diagnosis and relapse samples, combined with targeted sequencing, identified and isolated minor diagnosis subclones that initiate evolutionary trajectory toward relapse (termed diagnosis Relapse Initiating clones, dRI). Compared to other diagnosis subclones, dRI were drug tolerant with distinct engraftment and metabolic properties. Transciptionally, dRI displayed enrichment for chromatin remodelling, mitochondrial metabolism, proteostasis programs and an increase in stemness pathways. The isolation and characterization of dRI subclones reveals new avenues for eradicating dRI cells by targeting their distinct metabolic and transcriptional pathways before further evolution renders them fully therapy resistant.

摘要

: 疾病复发导致 B-祖细胞急性淋巴细胞白血病 (B-ALL) 的显著死亡率。匹配诊断和复发样本的基因组分析显示复发常由次要诊断亚克隆引起。然而,为什么治疗根除一些亚克隆而另一些亚克隆存活并进展至复发仍不清楚。阐明这些不同命运的机制需要对分离的亚克隆进行功能分析。在这里,大规模限制稀释异种移植诊断和复发样本,结合靶向测序,鉴定和分离启动向复发进化轨迹的次要诊断亚克隆 (称为诊断复发启动克隆, dRI)。与其他诊断亚克隆相比,dRI 具有不同的植入和代谢特性的药物耐受性。从转运角度来看,dRI 显示了染色质重塑、线粒体代谢、蛋白停滞程序和干性通路增加的富集。DRI 亚克隆隔离和表征揭示了在进一步进化使 dRI 细胞完全耐药之前,通过靶向其不同的代谢和转录途径根除 dRI 细胞的新途径。

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DOI:10.1016/j.canlet.2019.12.039
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