Abstract：
BACKGROUND: The molecular pathogenesis of acute myeloid leukemia (AML) was dramatically clarified over the latest two decades. Several important molecular markers were discovered in patients with AML that have helped to improve the risk stratification. However, developing new treatment strategies for relapsed/refractory acute myeloid leukemia (AML) is crucial due to its poor prognosis.
METHODS: To overcome this difficulty, we performed an assay for transposase-accessible chromatin with sequencing (ATAC-seq) in 10 AML patients with various gene alterations. ATAC-seq is based on direct in vitro sequencing adaptor transposition into native chromatin, and is a rapid and sensitive method for integrative epigenomic analysis. ATAC-seq analysis revealed increased accessibility of the DOCK1 gene in patients with AML harboring poor prognostic factors. Following the ATAC-seq results, quantitative reverse transcription polymerase chain reaction was used to measure DOCK1 gene expression levels in 369 pediatric patients with de novo AML.
RESULTS: High DOCK1 expression was detected in 132 (37%) patients. The overall survival (OS) and event-free survival (EFS) among patients with high DOCK1 expression were significantly worse than those patients with low DOCK1 expression (3-year EFS: 34% vs. 60%, p < .001 and 3-year OS: 60% vs. 80%, p < .001). To investigate the significance of high DOCK1 gene expression, we transduced DOCK1 into MOLM14 cells, and revealed that cytarabine in combination with DOCK1 inhibitor reduced the viability of these leukemic cells.
CONCLUSIONS: Our results indicate that a DOCK1 inhibitor might reinforce the effects of cytarabine and other anti-cancer agents in patients with AML with high DOCK1 expression.
METHODS: To overcome this difficulty, we performed an assay for transposase-accessible chromatin with sequencing (ATAC-seq) in 10 AML patients with various gene alterations. ATAC-seq is based on direct in vitro sequencing adaptor transposition into native chromatin, and is a rapid and sensitive method for integrative epigenomic analysis. ATAC-seq analysis revealed increased accessibility of the DOCK1 gene in patients with AML harboring poor prognostic factors. Following the ATAC-seq results, quantitative reverse transcription polymerase chain reaction was used to measure DOCK1 gene expression levels in 369 pediatric patients with de novo AML.
RESULTS: High DOCK1 expression was detected in 132 (37%) patients. The overall survival (OS) and event-free survival (EFS) among patients with high DOCK1 expression were significantly worse than those patients with low DOCK1 expression (3-year EFS: 34% vs. 60%, p < .001 and 3-year OS: 60% vs. 80%, p < .001). To investigate the significance of high DOCK1 gene expression, we transduced DOCK1 into MOLM14 cells, and revealed that cytarabine in combination with DOCK1 inhibitor reduced the viability of these leukemic cells.
CONCLUSIONS: Our results indicate that a DOCK1 inhibitor might reinforce the effects of cytarabine and other anti-cancer agents in patients with AML with high DOCK1 expression.
摘要：
背景：在最近的二十年中，急性髓细胞性白血病（AML）的分子发病机制得到了极大的阐明。在AML患者中发现了一些重要的分子标志物，这些标志物有助于改善风险分层。然而,由于复发/难治性急性髓系白血病(AML)预后不良,因此开发新的治疗策略至关重要.
方法：为了克服这个困难，我们对10例有各种基因改变的AML患者进行了转座酶可接近的染色质测序分析(ATAC-seq).ATAC-seq基于直接体外测序衔接子转座到天然染色质中，是一种快速、灵敏的整合表观基因组分析方法。ATAC-seq分析显示，在预后不良的AML患者中，DOCK1基因的可及性增加。根据ATAC-seq结果，采用定量逆转录聚合酶链反应检测369例初发AML患儿DOCK1基因表达水平.
结果：在132例（37%）患者中检测到高DOCK1表达。DOCK1高表达患者的总生存率（OS）和无事件生存率（EFS）明显低于DOCK1低表达患者（3年EFS：34％vs.60%,p<.001和3年OS：60%与80%,p<.001)。探讨DOCK1基因高表达的意义,我们将DOCK1转导到MOLM14细胞中，并显示阿糖胞苷与DOCK1抑制剂的组合降低了这些白血病细胞的活力。
结论：我们的结果表明，DOCK1抑制剂可能会增强阿糖胞苷和其他抗癌药物在DOCK1高表达的AML患者中的作用。
方法：为了克服这个困难，我们对10例有各种基因改变的AML患者进行了转座酶可接近的染色质测序分析(ATAC-seq).ATAC-seq基于直接体外测序衔接子转座到天然染色质中，是一种快速、灵敏的整合表观基因组分析方法。ATAC-seq分析显示，在预后不良的AML患者中，DOCK1基因的可及性增加。根据ATAC-seq结果，采用定量逆转录聚合酶链反应检测369例初发AML患儿DOCK1基因表达水平.
结果：在132例（37%）患者中检测到高DOCK1表达。DOCK1高表达患者的总生存率（OS）和无事件生存率（EFS）明显低于DOCK1低表达患者（3年EFS：34％vs.60%,p<.001和3年OS：60%与80%,p<.001)。探讨DOCK1基因高表达的意义,我们将DOCK1转导到MOLM14细胞中，并显示阿糖胞苷与DOCK1抑制剂的组合降低了这些白血病细胞的活力。
结论：我们的结果表明，DOCK1抑制剂可能会增强阿糖胞苷和其他抗癌药物在DOCK1高表达的AML患者中的作用。
