Institute of Hematology and Blood Transfusion, Prague, Czech Republic.
Eur J Haematol. 2012 Feb;88(2):128-35. doi: 10.1111/j.1600-0609.2011.01716.x. Epub 2011 Nov 17.
Recently, mutations in DNMT3A gene have been described in about 25% acute myeloid leukemia (AML) cases, preferentially in monocytic AML. They were found to predict worse overall survival (OS) of mutated patients.
RT-PCR followed by direct sequencing was used to test the presence of DNMT3A mutations in 226 AML patients with an intermediate-risk (IR) cytogenetics.
Sixty-seven patients of 226 (29.6%) carried a mutation in the DNMT3A gene. Occurrence of DNMT3A mutations was associated with female sex (P = 0.027) and with the presence of FLT3/ITD (P = 0.003), but not with particular FAB subtypes. Patients with DNMT3A mutation had higher initial WBC counts than those without it (P = 0.064) only because of higher incidence of FLT3/ITD within these cases. There was no difference between mutated and wild-type groups in reaching complete remission (CR) (P = 0.380). OS was not affected by DNMT3A mutation (P = 0.251), but OS of patients who reached CR was longer in DNMT3A negative cases (P = 0.025). Patients with DNMT3A mutation had a higher relapse rate (P = 0.007). Patients carrying both the DNMT3A mutation and FLT3/ITD relapsed more often than either patients with single DNMT3A mutation (P = 0.044) or patients with FLT3/ITD only (P = 0.058). DNMT3A mutations were associated with higher relapse rate even within the FLT3/ITD-negative group (P = 0.072). After reaching CR, these two genetic factors were independent predictors of relapse at multivariate analysis (P < 0.001). Only three of 30 'double-mutated' (FLT3/ITD+, DNMT3A+) patients are still alive, all of them having undergone hematopoietic stem cell transplant.
We have confirmed the high incidence of DNMT3A mutations in patients with AML with IR cytogenetics. Patients with DNMT3A mutations relapse more often and have inferior OS when only patients achieving CR are analyzed. 'Double-mutated' patients have a very poor prognosis.
最近，DNMT3A 基因突变已在约 25%的急性髓系白血病（AML）病例中，尤其是在单核细胞性 AML 中被描述。它们被发现可预测突变患者的总体生存（OS）较差。
使用 RT-PCR 后直接测序法对 226 例具有中危（IR）细胞遗传学的 AML 患者进行 DNMT3A 基因突变检测。
226 例患者中有 67 例（29.6%）携带 DNMT3A 基因突变。DNMT3A 基因突变的发生与女性（P = 0.027）和存在 FLT3/ITD（P = 0.003）有关，但与特定的 FAB 亚型无关。DNMT3A 突变患者的初始白细胞计数高于无突变患者（P = 0.064），这仅仅是因为这些病例中 FLT3/ITD 的发生率更高。在达到完全缓解（CR）的患者中，突变组和野生型组之间在达到 CR 方面没有差异（P = 0.380）。DNMT3A 突变对 OS 没有影响（P = 0.251），但在 DNMT3A 阴性病例中，达到 CR 的患者的 OS 更长（P = 0.025）。DNMT3A 突变患者的复发率更高（P = 0.007）。携带 DNMT3A 突变和 FLT3/ITD 的患者比仅携带单一 DNMT3A 突变的患者（P = 0.044）或仅携带 FLT3/ITD 的患者（P = 0.058）更常复发。即使在 FLT3/ITD 阴性组中，DNMT3A 突变也与更高的复发率相关（P = 0.072）。在多变量分析中，达到 CR 后，这两个遗传因素是复发的独立预测因素（P <0.001）。在 30 名“双突变”（FLT3/ITD+，DNMT3A+）患者中，只有 3 名仍然存活，他们均接受了造血干细胞移植。
我们已经证实，在具有 IR 细胞遗传学的 AML 患者中，DNMT3A 基因突变的发生率很高。仅分析达到 CR 的患者时，携带 DNMT3A 突变的患者复发更多，OS 更差。“双突变”患者预后极差。
