急性髓系白血病患者中 DNMT3A、FLT3 和 NPM1 基因突变的预后影响。
Prognostic Impact of Concurrent DNMT3A, FLT3 and NPM1 Gene Mutations in Acute Myeloid Leukemia Patients.
机构信息
Department of Clinical Pathology, Faculty of Medicine, Zagazig University, Zagazig, Egypt.
Department of Clinical Pathology, National Cancer Institute, Cairo University, Cairo, Egypt.
出版信息
Clin Lymphoma Myeloma Leuk. 2021 Dec;21(12):e960-e969. doi: 10.1016/j.clml.2021.07.011. Epub 2021 Jul 16.
BACKGROUND
Acute myeloid leukemia (AML) is one of the rapidly progressing malignancies which is characterized by unregulated proliferation of hematopoietic precursors. Technological improvements enhanced the availability of genetic AML biomarkers. The clinical relevance of these molecular markers for AML diagnosis, planning of therapy and risk stratification are increasing evidently.
METHODS
In current study, one hundred newly diagnosed AML patients before receiving induction chemotherapy were included, they were subjected to clinical examination, cytochemical and morphological analysis of blood cells, flow cytometric, cytogenetic and molecular genetic analysis for detection of NPM1, FLT3-ITD and DNMT3A mutations. Direct sequencing analysis for detection of NPM1 and DNMT3A genes mutations were done. FLT3 /ITD gene mutation was detected by gel electrophoresis after PCR amplification.
RESULTS
According to genetic markers, our AML patients are classified in to further 8groups. AML patients with three DNMT3A/FLT3/NPM1 gene mutations (AML ) this group of patients presented with a heavy disease burden, had an elevated WBC in comparison to other groups (70 vs. 41 × 10/μL; P = .019), and BM blast counts (71% vs. 55.6%, P < .02). When comparing eight groups for death event there were significant difference among groups; P = .005, group 1 (AML ) showed rapid decline of the cumulative overall survival. There was a significant difference among 8 groups as regards response to treatment after 14 days (P = .02), group 7 AML with (DNMT3A +NMP1) gene mutations showed better response to treatment (100%), groups 1 and 3 AML with (NPM1+DNMT3A +NMP1) gene mutations and AML with isolated FLT3-ITD showed no response to treatment after 14 days. And as regards response to treatment after 28 days, the eight groups showed no significant difference (P = .14).
CONCLUSION
Our study supports adverse prognostic effect of presence of DNMT3A gene mutation either alone or in the presence of FLT3 and/or NPM1 gene mutations.
背景
急性髓细胞白血病（AML）是一种恶性肿瘤，其特征是造血前体细胞的不受控制的增殖。技术的进步提高了遗传 AML 生物标志物的可用性。这些分子标志物在 AML 诊断、治疗计划和风险分层中的临床相关性明显增加。
方法
在目前的研究中，纳入了 100 名新诊断的 AML 患者，这些患者在接受诱导化疗前接受了临床检查、血细胞的细胞化学和形态学分析、流式细胞术、细胞遗传学和分子遗传学分析，以检测 NPM1、FLT3-ITD 和 DNMT3A 突变。进行直接测序分析以检测 NPM1 和 DNMT3A 基因突变。通过 PCR 扩增后凝胶电泳检测 FLT3/ITD 基因突变。
结果
根据遗传标志物，我们的 AML 患者被进一步分为 8 组。AML 患者存在三种 DNMT3A/FLT3/NPM1 基因突变（AML ），这组患者疾病负担较重，与其他组相比白细胞计数较高（70 对 41×10/μL；P=0.019），骨髓原始细胞计数较高（71%对 55.6%，P<.02）。当比较 8 组的死亡事件时，组间有显著差异；P=0.005，组 1（AML ）的累积总生存率迅速下降。在治疗 14 天后的反应方面，8 组之间存在显著差异（P=0.02），AML 中存在（DNMT3A+NMP1）基因突变的组 7 反应更好（100%），AML 中存在（NPM1+DNMT3A+NMP1）基因突变和 AML 中存在孤立的 FLT3-ITD 的组 1 和 3 对治疗无反应在 14 天后。在治疗 28 天后，8 组之间无显著差异（P=0.14）。
结论
我们的研究支持 DNMT3A 基因突变的存在具有不良预后效应，无论是单独存在还是与 FLT3 和/或 NPM1 基因突变同时存在。
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