The addition of the proteasome inhibitor bortezomib to standard chemotherapy did not improve survival in pediatric acute myeloid leukemia (AML) when all patients were analyzed as a group in the Children’s Oncology Group phase 3 trial AAML1031 (NCT01371981). Proteasome inhibition influences the chromatin landscape and proteostasis, and we hypothesized that baseline proteomic analysis of histone- and chromatin-modifying enzymes (HMEs) would identify AML subgroups that benefitted from bortezomib addition. A proteomic profile of 483 patients treated with AAML1031 chemotherapy was generated using a reverse-phase protein array. A relatively high expression of 16 HME was associated with lower EFS and higher 3-year relapse risk after AML standard treatment compared to low expressions (52% vs. 29%,p= 0.005). The high-HME profile correlated with more transposase-accessible chromatin, as demonstrated via ATAC-sequencing, and the bortezomib addition improved the 3-year overall survival compared with standard therapy (62% vs. 75%,p= 0.033). These data suggest that there are pediatric AML populations that respond well to bortezomib-containing chemotherapy.
在儿童肿瘤学组三期临床试验AAML1031（NCT01371981）中，当对所有患者进行整体分析时，蛋白酶体抑制剂硼替佐米联合标准化疗方案并未改善儿童急性髓系白血病（AML）患者的生存率。蛋白酶体抑制会影响染色质景观和蛋白质稳态，我们推测通过对组蛋白及染色质修饰酶（HMEs）进行基线蛋白质组学分析，能够识别出可从硼替佐米联合治疗中获益的AML亚群。本研究采用反相蛋白质芯片技术对483例接受AAML1031化疗的患者进行了蛋白质组学分析。结果显示，与低表达组相比，16种HMEs相对高表达与AML标准治疗后较低的无事件生存率及较高的3年复发风险相关（52% vs. 29%，p=0.005）。通过ATAC测序技术证实，高HME特征与更高的转座酶可及染色质水平相关，且硼替佐米联合治疗组的3年总生存率较标准治疗组显著提升（62% vs. 75%，p=0.033）。这些数据表明，存在对含硼替佐米化疗方案反应良好的儿童AML患者亚群。
肿瘤(癌症)患者之家