Xue Meng-xing, Qiu Hui-ying, Feng Yu-feng, Zhu Zi-ling, Chang Wei-rong, Liang Jian-ying, Chen Su-ning, Cen Jian-nong, Xue Yong-quan, Liu Yue-jun, Sun Ai-ning, Wu De-pei
The First Affiliated Hospital of Soochow University, Jiangsu Institute of Hematology, Key Laboratory of Thrombosis and Hemostasis, Ministry of Health, Suzhou 215006, China.
Zhonghua Xue Ye Xue Za Zhi. 2008 Nov;29(11):757-61.
To evaluate the prevalence of Fms-Like tyrosine kinase 3 (FLT3) mutations including internal tandem duplication (ITD) of juxtamembrane region and point mutation in the second tyrosine kinase domain (TKD) in acute promyelocytic leukemia (APL) and its clinical significance.
Bone marrow mononuclear cells from 160 newly diagnosed APL patients were analyzed. Polymerase chain reaction (PCR) was used to detect FLT3-ITD mutations, FLT3-ITD positive samples were further analyzed for the ITD allelic ratio (ITD-AR, mutant-wild type ratio). The FLT3-TKD mutation was analyzed by PCR amplification of exon 20 followed by EcoR V digestion and sequencing.
Out of 160 patients, 30 (18.75%) patients were FLT3-ITD positive, 17 (10.62%) were FLT3-TKD positive, 2 had both of mutations. The initial WBC count and the ratio of short type PML-RAR alpha isoforms in FLT3-ITD positive and FLT3-TKD positive patients were all higher than that in patients with wild-type FLT3 (FLT3-wt) (P < 0.05). For FLT3-ITD positive patients, the incidences of retinoic acid syndrome (RAS) and disseminated intravascular coagulation (DIC) were 41.7% and 65.4%, respectively, being higher than that of FLT3-wt patients, while their complete remission (CR) rate was lower (69.2% vs 90.3%, P < 0.05). For FLT3-TKD positive patients, the incidence of RAS, DIC and CR rate were not significantly different from that of FLT3-wt patients (P > 0.05). FLT3-ITD positive patients had a shorter overall survival (OS) (P < 0.05), but not disease-free survival (DFS) (P > 0.05) as compared with FLT3-wt patients. There was no significant difference in either OS or DFS between FLT3-TKD positive and FLT3-wt patients. The ITD-AR of 30 FLT3-ITD positive patients varied from 0.11 to 6.55 with a median of 1.0. The initial WBC count, incidence of RAS and DIC, CR rate were not significantly different between the patients with ITD-AR greater than 1.0 and lower than 1.0 (P > 0.05).
FLT3 mutations (FLT3-ITD or FLT3-TKD) are frequently identified in patients with newly diagnosed APL, both mutations are associated with higher initial WBC and short type PML-RAR alpha isoforms. FLT3-ITD mutation is more frequent than FLT3-TKD mutation, and predicts a poorer prognosis, whereas FLT3-TKD mutation does not show the same unfavorable prognostic effect on APL patients.
评估急性早幼粒细胞白血病（APL）中Fms样酪氨酸激酶3（FLT3）突变的发生率，包括近膜区内部串联重复（ITD）和第二个酪氨酸激酶结构域（TKD）的点突变，并探讨其临床意义。
对160例新诊断的APL患者的骨髓单个核细胞进行分析。采用聚合酶链反应（PCR）检测FLT3-ITD突变，对FLT3-ITD阳性样本进一步分析ITD等位基因比例（ITD-AR，突变型-野生型比例）。通过对第20外显子进行PCR扩增，随后进行EcoR V酶切和测序分析FLT3-TKD突变。
160例患者中，30例（18.75%）为FLT3-ITD阳性，17例（10.62%）为FLT3-TKD阳性，2例同时存在两种突变。FLT3-ITD阳性和FLT3-TKD阳性患者的初始白细胞计数及短型PML-RARα异构体比例均高于野生型FLT3（FLT3-wt）患者（P<0.05）。对于FLT3-ITD阳性患者，维甲酸综合征（RAS）和弥散性血管内凝血（DIC）的发生率分别为41.7%和65.4%，高于FLT3-wt患者，而其完全缓解（CR）率较低（69.2%对90.3%，P<0.05）。对于FLT3-TKD阳性患者，RAS、DIC的发生率及CR率与FLT3-wt患者相比差异无统计学意义（P>0.05）。与FLT3-wt患者相比，FLT3-ITD阳性患者的总生存期（OS）较短（P<0.05），但无病生存期（DFS）差异无统计学意义（P>0.05）。FLT3-TKD阳性与FLT3-wt患者的OS和DFS均无显著差异。30例FLT3-ITD阳性患者的ITD-AR为0.11至6.55，中位数为1.0。ITD-AR大于1.0和小于1.0的患者在初始白细胞计数、RAS和DIC发生率、CR率方面差异无统计学意义（P>0.05）。
新诊断的APL患者中经常发现FLT3突变（FLT3-ITD或FLT3-TKD），两种突变均与较高的初始白细胞计数和短型PML-RARα异构体相关。FLT3-ITD突变比FLT3-TKD突变更常见，且预示预后较差，而FLT3-TKD突变对APL患者未显示出同样不利的预后影响。
