Adult acute lymphoblastic leukemia (ALL) is associated with poor outcomes. ALL is initiated by primary aberrations, but secondary genetic lesions are necessary for overt ALL. In this study, we reassessed the value of primary and secondary aberrations in intensively treated ALL patients in relation to mutator enzyme expression. RT-PCR, genomic PCR, and sequencing were applied to evaluate primary aberrations, while qPCR was used to measure the expression of RAG and AID mutator enzymes in 166 adult ALL patients. Secondary copy number alterations (CNA) were studied in 94 cases by MLPA assay. Primary aberrations alone stratified 30% of the patients (27% high-risk, 3% low-risk cases). The remaining 70% intermediate-risk patients includedBCR::ABL1possubgroup and ALL lacking identified genetic markers (NEG ALL). We identified three CNA profiles: high-risk bad-CNA (CNAhigh/IKZF1pos), low-risk good-CNA (all other CNAs), and intermediate-risk CNAneg. Furthermore, based on RAG/AID expression, we report possible mechanisms underlying the CNA profiles associated with poor outcome: AID stratified outcome in CNAneg, which accompanied most likely a particular profile of single nucleotide variations, while RAG in CNAposincreased the odds for CNAhigh/IKZF1posdevelopment. Finally, we integrated primary genetic aberrations with CNA to propose a revised risk stratification code, which allowed us to stratify 75% ofBCR::ABL1posand NEG patients.
成人急性淋巴细胞白血病（ALL）的预后通常较差。该疾病由原发性遗传异常引发，但继发性遗传病变是显性ALL形成的必要条件。本研究重新评估了在强化治疗ALL患者中，原发性和继发性遗传异常与突变酶表达的相关性。我们采用RT-PCR、基因组PCR及测序技术对166例成人ALL患者的原发性异常进行评估，同时运用qPCR检测RAG和AID突变酶的表达水平。通过MLPA技术对其中94例患者的继发性拷贝数变异（CNA）进行分析。仅依据原发性异常可将30%的患者进行风险分层（27%高危，3%低危）。其余70%中危患者包括BCR::ABL1阳性亚组及未发现明确遗传标志的ALL（NEG ALL）。我们识别出三种CNA特征谱：高危不良CNA（CNA高表达/IKZF1阳性）、低危良好CNA（其他所有CNA类型）及中危CNA阴性组。进一步基于RAG/AID表达水平，我们揭示了与不良预后相关的CNA特征谱潜在机制：在CNA阴性组中，AID表达水平可预测预后，该组很可能伴随特定的单核苷酸变异特征；而在CNA阳性组中，RAG表达增加了发展为CNA高表达/IKZF1阳性的风险概率。最终，我们将原发性遗传异常与CNA整合，提出修订后的风险分层编码体系，该体系可对75%的BCR::ABL1阳性及NEG ALL患者实现有效分层。
肿瘤(癌症)患者之家