DNMT3A（R882）突变特征及其在与NPM1和FLT3突变共存的急性髓系白血病中的预后影响
DNMT3A (R882) mutation features and prognostic effect in acute myeloid leukemia in Coexistent with NPM1 and FLT3 mutations.
作者信息
Kumar Dushyant, Mehta Anurag, Panigrahi Manoj Kumar, Nath Sukanta, Saikia Kandarpa Kumar
机构信息
Dept of Bioengineering & Technology, Gauhati University, Guwahati 781014, India.
Rajiv Gandhi Cancer Institute and research Centre, New Delhi 110085, India.
出版信息
Hematol Oncol Stem Cell Ther. 2018 Jun;11(2):82-89. doi: 10.1016/j.hemonc.2017.09.004. Epub 2017 Oct 18.
OBJECTIVE/BACKGROUND: In the absence of high-risk cytogenetic, DNMT3A (DNA Methyltransferase 3a) mutation status has an impact on outcome in the presence of FLT3 (FMS-like Tyrosine Kinase3) and/or NPM1 (Nucleophosmin). In this study, we focus on the features and effect of DNMT3A (R882) mutation in acute myeloid leukemia (AML) in the presence or absence of NPM1 and FLT3 mutations.
METHODS
A total of 174 cytogenetically normal (CN)-AML cases were analyzed for NPM1, FLT3, and DNMT3A mutations. For NPM1 mutation detection, we used the pyrosequencing technique; for FLT3 mutations, polymerase chain reaction and RFLP with ECO-RV techniques were used, and for DNMT3A mutation analysis, we used Sanger sequencing and RFLP (Restriction Fragment Length Polymorphism) techniques.
RESULTS
NPM1 mutation was found in 40.80%, DNMT3A in 12.06%, and FLT3 mutation was found in 16.66% of 174 CN-AML patients. We also found seven cases which were (NPM1+, FLT3+), 10 cases which were (NPM1+, DNMT3A+), and two cases were found positive for (DNMT3A+, FLT3+) mutations. Adult patients had significantly higher frequency of NPM1 mutation than children (72.22% vs. 16.66%; p = .020), whereas FLT3/ITD and DNMT3A mutation was associated with higher white blood count (p = .081). Immunophenotypically, NPM1 and DNMT3A mutations were significantly associated with the lack of CD34, whereas FLT3/ITD mutation was positively associated with the expression of CD7. We also assessed the overall survival and progression-free survival of DNMT3A mutation status among patients with CN-AML. Indeed, DNMT3A mutations within the CN-AML subset were associated with significantly shorter overall survival and progression-free survival compared to NPM1 and FLT3 mutated patients (p = .067 and p = .065, respectively).
CONCLUSION
DNMT3A R882 mutation plays an important role in CN-AML patients' prognosis and clinical outcomes in the presence and absence of NPM1 and FLT3 mutations.
目的/背景：在不存在高风险细胞遗传学异常的情况下，DNMT3A（DNA甲基转移酶3a）突变状态会影响伴有FLT3（FMS样酪氨酸激酶3）和/或NPM1（核磷蛋白）异常时的预后。在本研究中，我们聚焦于急性髓系白血病（AML）中DNMT3A（R882）突变在存在或不存在NPM1和FLT3突变时的特征及影响。
方法
对174例细胞遗传学正常（CN）的AML病例进行NPM1、FLT3和DNMT3A突变分析。对于NPM1突变检测，我们采用焦磷酸测序技术；对于FLT3突变，采用聚合酶链反应和ECO - RV酶切片段长度多态性（RFLP）技术；对于DNMT3A突变分析，采用桑格测序和RFLP（限制性片段长度多态性）技术。
结果
在174例CN - AML患者中，发现NPM1突变的占40.80%，DNMT3A突变的占12.06%，FLT3突变的占16.66%。我们还发现7例（NPM1 +，FLT3 +），10例（NPM1 +，DNMT3A +），以及2例（DNMT3A +，FLT3 +）突变阳性。成年患者NPM1突变频率显著高于儿童（72.22%对16.66%；p = 0.020），而FLT3/内部串联重复（ITD）和DNMT3A突变与较高的白细胞计数相关（p = 0.081）。免疫表型分析显示，NPM1和DNMT3A突变与CD34缺失显著相关，而FLT3/ITD突变与CD7表达呈正相关。我们还评估了CN - AML患者中DNMT3A突变状态的总生存期和无进展生存期。事实上，与NPM1和FLT3突变患者相比，CN - AML亚组中的DNMT3A突变与显著更短的总生存期和无进展生存期相关（分别为p = 0.067和p = 0.065）。
结论
在存在和不存在NPM1和FLT3突变的情况下，DNMT3A R882突变在CN - AML患者的预后和临床结局中起着重要作用。
Zotero 插件