文章：

患者特异性循环肿瘤DNA用于监测婴儿白血病临床前模型中Menin抑制剂治疗反应

Patient-Specific Circulating Tumor DNA for Monitoring Response to Menin Inhibitor Treatment in Preclinical Models of Infant Leukemia

原文发布日期：28 November 2024

DOI: 10.3390/cancers16233990

类型: Article

开放获取: 是

英文摘要：

Background: In infantKMT2A(MLL1)-rearranged (MLL-r) acute lymphoblastic leukemia (ALL), early relapse and treatment response are currently monitored through invasive repeated bone marrow (BM) biopsies. Circulating tumor DNA (ctDNA) in peripheral blood (PB) provides a minimally invasive alternative, allowing for more frequent disease monitoring. However, a poor understanding of ctDNA dynamics has hampered its clinical translation. We explored the predictive value of ctDNA for detecting minimal/measurable residual disease (MRD) and drug response in a patient-derived xenograft (PDX) model of infant MLL-r ALL. Methods: Immune-deficient mice engrafted with three MLL-r ALL PDXs were monitored for ctDNA levels before and after treatment with the menin inhibitor SNDX-50469. Results: The amount of ctDNA detected strongly correlated with leukemia burden during initial engraftment prior to drug treatment. However, following SNDX-50469 treatment, the leukemic burden assessed by either PB leukemia cells through flow cytometry or ctDNA levels through droplet digital polymerase chain reaction (ddPCR) was discrepant. This divergence could be attributed to the persistence of leukemia cells in the spleen and BM, highlighting the ability of ctDNA to reflect disease dynamics in key leukemia infiltration sites. Conclusions: Notably, ctDNA analysis proved to be a superior predictor of MRD compared to PB assessment alone, especially in instances of low disease burden. These findings highlight the potential of ctDNA as a sensitive biomarker for monitoring treatment response and detecting MRD in infant MLL-r ALL.

摘要翻译： 

背景：在婴儿KMT2A（MLL1）重排急性淋巴细胞白血病中，目前通过侵入性重复骨髓活检监测早期复发和治疗反应。外周血中的循环肿瘤DNA提供了一种微创替代方案，可实现更频繁的疾病监测。然而，对ctDNA动态变化的了解不足阻碍了其临床转化。我们在婴儿MLL重排ALL的患者来源异种移植模型中探索了ctDNA检测微小/可测量残留病及药物反应的预测价值。方法：对移植三种MLL重排ALL PDX的免疫缺陷小鼠，在menin抑制剂SNDX-50469治疗前后监测ctDNA水平。结果：药物治疗前初始移植阶段检测到的ctDNA量与白血病负荷呈强相关。然而，SNDX-50469治疗后，通过流式细胞术检测的外周血白血病细胞与通过微滴数字PCR检测的ctDNA水平呈现差异。这种差异可归因于脾脏和骨髓中白血病细胞的持续存在，凸显了ctDNA反映关键白血病浸润部位疾病动态的能力。结论：值得注意的是，与单纯外周血评估相比，ctDNA分析被证明是更优的MRD预测指标，尤其在疾病负荷较低的情况下。这些发现凸显了ctDNA作为监测婴儿MLL重排ALL治疗反应和检测MRD的敏感生物标志物的潜力。

原文链接：

Patient-Specific Circulating Tumor DNA for Monitoring Response to Menin Inhibitor Treatment in Preclinical Models of Infant Leukemia