PDF(Pubmed)
Abstract：
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 included BCR::ABL1pos subgroup 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 CNApos increased the odds for CNAhigh/IKZF1pos development. Finally, we integrated primary genetic aberrations with CNA to propose a revised risk stratification code, which allowed us to stratify 75% of BCR::ABL1pos and NEG patients.
摘要：
成人急性淋巴细胞白血病（ALL）与不良预后相关。ALL由主畸变启动，但继发性遗传损伤是明显的全部所必需的。在这项研究中,我们重新评估了强化治疗的ALL患者的原发性和继发性畸变与突变酶表达的关系。RT-PCR,基因组PCR,测序用于评估原发性畸变，而qPCR用于检测166例成年ALL患者中RAG和AID突变酶的表达。通过MLPA测定法研究了94例二次拷贝数改变（CNA）。仅原发性畸变就对30％的患者进行了分层（27％的高危患者，3%低风险病例)。其余70%的中危患者包括BCR::ABL1pos亚组和缺乏遗传标记的ALL(NEGALL)。我们确定了三个CNA概况：高风险不良CNA（CNAmigh/IKZF1pos），低风险商品CNA(所有其他CNA)，和中等风险CNAneg。此外，基于RAG/AID表达式，我们报告了CNA概况与不良结局相关的可能机制：CNAneg的AID分层结局，最可能伴随着单核苷酸变异的特定特征，而CNApos中的RAG增加了CNAhigh/IKZF1pos开发的几率。最后,我们将主要遗传畸变与CNA整合，提出修订的风险分层代码，这使我们能够对75%的BCR::ABL1pos和NEG患者进行分层。
