文章：

成人B细胞急性淋巴细胞白血病复发倾向的遗传通路研究

Preferential Genetic Pathways Lead to Relapses in Adult B-Cell Acute Lymphoblastic Leukemia

原文发布日期：17 December 2024

DOI: 10.3390/cancers16244200

类型: Article

开放获取: 是

英文摘要：

Adult B-cell acute lymphoblastic leukemia (B-ALL) is characterized by genetic heterogeneity and a high relapse rate, affecting over 40% of adults. However, the mechanisms leading to relapse in adults are poorly understood. Forty-four adult B-ALL patients were studied at both diagnosis and relapse by next-generation sequencing (NGS). Four main genetic pathways leading to relapse in adults were identified:IKZF1plusgenetic profile,RASmutations andTP53alterations in Ph-negative B-ALL and acquisition ofABL1mutations in Ph-positive patients. The most frequently deleted gene at diagnosis wasIKZF1(52%), and 70% of these patients hadIKZF1plusprofile. Notably, 88% of patients withIKZF1plusat diagnosis retained this genetic profile at relapse. Conversely, the acquisition ofRASmutations or the expansion of subclones (normalized variant allele frequency < 25%) present from diagnosis were observed in 24% of Ph-negative patients at relapse. In addition, 24% of relapses in the Ph-negative cohort could potentially be driven byTP53alterations. Of these cases, five presented from diagnosis, and four emerged at relapse, mostly as “double-hit” events involving bothTP53deletion and mutation. In Ph-positive B-ALL, the main genetic finding at relapse was the acquisition ofABL1mutations (86%). Three clonal evolution patterns were identified: the persistent clone trajectory (25%), the expanding clone trajectory (11%) and the therapy-boosted trajectory (48%). Our results reveal the presence of preferential biological pathways leading to relapse in adult B-ALL. These findings underscore the need for personalized therapeutic strategies to improve clinical outcomes in adult patients with B-ALL.

摘要翻译： 

成人B细胞急性淋巴细胞白血病（B-ALL）具有遗传异质性高、复发率高的特点，超过40%的成人患者会出现复发。然而，导致成人患者复发的机制尚不明确。本研究通过二代测序技术对44例成人B-ALL患者在初诊及复发阶段进行了分析，揭示了导致成人患者复发的四条主要遗传学通路：IKZF1plus遗传谱系、Ph阴性B-ALL中的RAS突变与TP53改变，以及Ph阳性患者中ABL1突变的获得。初诊时最常见的基因缺失为IKZF1（52%），其中70%的患者呈现IKZF1plus谱系。值得注意的是，88%初诊时具有IKZF1plus谱系的患者在复发时仍保留该遗传特征。相反，在24%的Ph阴性复发患者中观察到RAS突变的获得或初诊时已存在的亚克隆扩增（标准化变异等位基因频率<25%）。此外，Ph阴性队列中24%的复发可能由TP53改变驱动，其中5例在初诊时即存在，4例在复发时新发，且多数表现为同时涉及TP53缺失与突变的"双重打击"事件。在Ph阳性B-ALL中，复发时最主要的遗传学发现是ABL1突变的获得（86%）。研究识别出三种克隆演化模式：持续克隆轨迹（25%）、扩增克隆轨迹（11%）和治疗促进轨迹（48%）。本研究结果揭示了成人B-ALL复发存在倾向性生物学通路，这些发现强调了个体化治疗策略对改善成人B-ALL患者临床结局的必要性。

原文链接：

Preferential Genetic Pathways Lead to Relapses in Adult B-Cell Acute Lymphoblastic Leukemia