2nd Faculty of Medicine, Department of Pediatric Hematology and Oncology, Charles University and University Hospital Motol, Prague, Czech Republic.
Pediatr Blood Cancer. 2013 Mar;60(3):420-7. doi: 10.1002/pbc.24299. Epub 2012 Sep 19.
Recently, several studies have demonstrated a negative prognostic impact of Ikaros (IKZF1) gene alterations in acute lymphoblastic leukemia (ALL). However, controversies still exist regarding the impact of IKZF1 in current treatment protocols.
We simultaneously detected IKZF1 gene deletions by multiplex ligation-dependent probe amplification and gene expression of IKZF1 isoforms in 206 children with BCR/ABL-negative ALL treated with ALL IC-BFM 2002 protocol, in which risk stratification was not based on minimal residual disease (MRD), and validated the results on a cohort of 189 patients treated with MRD-directed ALL-BFM 2000 protocol.
Deletion of IKZF1 was present in 14 of 206 (7%) ALL IC patients. Interestingly, gene expression did not completely correlate with the deletion status in either cohort. Deletions were not always reflected in the gene expression of dominant-negative isoforms, and conversely, 7 of 395 (2%) non-deleted cases overexpressed dominant-negative isoform Ik6. IKZF1 deletions significantly affected event-free survival (EFS) of the ALL IC cohort (41 ± 14% vs. 86 ± 3%, P < 0.0001). Regarding IKZF1 isoforms, only Ik6 overexpression had negative prognostic impact (EFS 50 ± 16% vs. 85 ± 3%, P = 0.003). In multivariate analysis, which included ALL IC risk criteria, flow-cytometric MRD and IKZF1 alterations, day 15 MRD and IKZF1 deletion status displayed an independent prognostic impact.
We show that MRD-directed treatment diminishes prognostic impact of IKZF1 alterations. However, IKZF1 status alone or combined with day 15 flow cytometry can significantly improve risk stratification within BFM protocols at centers that do not perform antigen-receptor-based MRD monitoring.
最近，几项研究表明 Ikaros（IKZF1）基因改变对急性淋巴细胞白血病（ALL）有负面预后影响。然而，关于 IKZF1 在当前治疗方案中的影响仍存在争议。
我们同时通过多重连接依赖探针扩增检测 206 例接受 ALL IC-BFM 2002 方案治疗的 BCR/ABL 阴性 ALL 儿童的 IKZF1 基因缺失，并检测 IKZF1 同工型的基因表达，其中风险分层不基于微小残留病（MRD），并在接受 MRD 指导的 ALL-BFM 2000 方案治疗的 189 例患者队列中验证了结果。
在 206 例 ALL IC 患者中，有 14 例存在 IKZF1 缺失。有趣的是，两个队列中的基因表达并不完全与缺失状态相关。缺失并不总是反映在显性负性同工型 Ik6 的基因表达中，相反，395 例非缺失病例中有 7 例过表达显性负性同工型 Ik6。IKZF1 缺失显著影响 ALL IC 队列的无事件生存（EFS）（41±14% vs. 86±3%，P<0.0001）。关于 IKZF1 同工型，只有 Ik6 过表达具有负面预后影响（EFS 50±16% vs. 85±3%，P=0.003）。在包括 ALL IC 风险标准、流式细胞术 MRD 和 IKZF1 改变在内的多变量分析中，第 15 天 MRD 和 IKZF1 缺失状态显示出独立的预后影响。
我们表明，MRD 导向的治疗可降低 IKZF1 改变的预后影响。然而，在不进行抗原受体 MRD 监测的中心，IKZF1 状态单独或与第 15 天流式细胞术结合使用，可显著改善 BFM 方案中的风险分层。
