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.

中文翻译：

---

急性 B 系白血病的复发性潜伏诊断亚克隆具有耐药性并具有独特的代谢程序。


疾病复发会导致 B 祖细胞急性淋巴细胞白血病 (B-ALL) 显着死亡。对匹配的诊断和复发样本的基因组分析显示，复发通常是由次要诊断亚克隆引起的。然而，为什么治疗会根除一些亚克隆，而另一些亚克隆却能存活下来并进展到复发，这仍然不清楚。阐明这些不同命运背后的机制需要对分离的亚克隆进行功能分析。在这里，诊断和复发样本的大规模有限稀释异种移植，结合靶向测序，鉴定并分离了启动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 具有耐药性，具有独特的植入和代谢特性。从转录角度来看，dRI 显示出染色质重塑、线粒体代谢、蛋白质稳态程序的富集和干性途径的增加。 dRI 亚克隆的分离和表征揭示了在进一步进化使它们完全产生治疗抗性之前通过靶向其独特的代谢和转录途径来根除 dRI 细胞的新途径。