Analysis of FLT3-activating mutations in 979 patients with acute myelogenous leukemia:: association with FAB subtypes and identification of subgroups with poor prognosis
Analysis of FLT3-activating mutations in 979 patients with acute myelogenous leukemia:: association with FAB subtypes and identification of subgroups with poor prognosis
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DOI：
10.1182/blood.v99.12.4326
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发表时间：
2002-06-15
期刊：
影响因子：
20.3
通讯作者：
Illmer, T
中科院分区：
文献类型：
--
作者：
Thiede, C;Steudel, C;Illmer, T
在急性髓性白血病（AML）患者中，已经描述了FLT 3受体酪氨酸激酶的组成性激活，无论是通过内膜区域的内部串联重复（ITD）还是通过第二酪氨酸激酶结构域（TKD）的点突变。我们分析了979例AML患者中FLT 3突变的患病率和潜在预后影响。结果与细胞遗传学数据和临床反应相关。20.4%的患者发现FLT 3-ITD突变，7.7%的患者发现FLT 3-TKD突变。每种突变都与相似的临床特征相关，并且在核型正常的患者中更普遍。FAB M5患者中FLT 3畸变显著更多，FAB M2和M6患者中FLT 3畸变较少。虽然在细胞遗传学畸变患者中不太常见，但在42例t（15;17）患者中有13例和10例t（6;9）患者中有9例发现FLT 3-ITD。ITD等位基因在DNA水平上的患病率是异质性的，范围从一些患者的微弱突变带到其他患者的主要突变带。基于定量分析，突变体-野生型（wt）比率范围为0.03至32.56（中值，0.78）。突变体/野生型比值高（即大于0.78）的患者总体生存期和无病生存期显著缩短，而比值低于0.78的患者的生存期与无FLT 3畸变的患者无差异。多变量分析证实，高突变/野生型比例是一个强有力的独立预后因素。总之，这些数据证实FLT突变代表成人AML中的常见改变。组成性激活可能与单核细胞样分化有关。ITD阳性患者的高突变/wt比率似乎对预后相关性有重大影响。（血。2002;99：4326-4335）。(C)2002年，美国血液学会。
Constitutive activation of the FLT3 receptor tyrosine kinase, either by internal tandem duplication (ITD) of the juxtamembrane region or by point mutations in the second tyrosine kinase domain (TKD), has been described in patients with acute myelogenous leukemia (AML). We analyzed the prevalence and the potential prognostic impact of FLT3 mutations in 979 AML patients. Results were correlated with cytogenetic data and the clinical response. FLT3-ITD mutations were found in 20.4% and FLT3-TKD mutations in 7.7% of the patients. Each mutation was associated with similar clinical characteristics and was more prevalent in patients with normal karyotype. Significantly more FLT3 aberrations were found in patients with FAB M5, and fewer were found in patients with FAB M2 and M6. Although less frequent in patients with cytogenetic aberrations, FLT3-ITDs were found in 13 of 42 patients with t(15;17) and in 9 of 10 patients with t(6;9). The prevalence of the ITD allele on the DNA level was heterogeneous, ranging from faint mutant bands in some patients to predominant mutant bands in others. Based on quantitative analysis, the mutant-wild-type (wt) ratio ranged from 0.03 to 32.56 (median, 0.78). Patients with a high mutant/wt ratio (ie, greater than 0.78) had significantly shorter overall and disease-free survival, whereas survival in patients with ratios below 0.78 did not differ from those without FLT3 aberrations. Multivariate analysis confirmed a high mutant/wt ratio to be a strong independent prognostic factor. Taken together, these data confirm that FLT mutations represent a common alteration in adult AML. Constitutive activation may be associated with monocytoid differentiation. A high mutant/wt ratio in ITD-positive patients appears to have a major impact on the prognostic relevance. (Blood. 2002;99:4326-4335). (C) 2002 by The American Society of Hematology.