Stability and prognostic influence of FLT3 mutations in paired initial and relapsed AML samples
Stability and prognostic influence of FLT3 mutations in paired initial and relapsed AML samples
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DOI：
10.1038/sj.leu.2404246
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发表时间：
2006-07-01
期刊：
影响因子：
11.4
通讯作者：
Kaspers, G. J. L.
中科院分区：
文献类型：
--
作者：
Cloos, J.;Goemans, B. F.;Kaspers, G. J. L.
在急性髓系白血病 (AML) 中，fms 样酪氨酸激酶 3 (FLT3) 基因的激活突变可预测不良预后。我们在 80 名儿童和成人 AML 患者的配对初始和复发样本中确定了 FLT3 内部串联重复 (FLT3/ITD) 和 D835 点突变。在最初的儿科 AML 样本中发现了一个 D835 点突变。 Fms 样酪氨酸激酶 3/ITD 存在于 21 个初始样本和 22 个复发样本中（分别为 26.3% 和 27.5%）。有趣的是，FLT3/ITD 阳性与复发时间显着缩短相关，当复发时发现 ITD 阳性状态时最为明显（P < 0.001）。然而，14 例患者的 FLT3/ITD 状态在诊断和复发之间发生了变化。在 4 名患者中，FLT3/ITD 在复发时检测不到；在 5 名患者中，FLT3/ITD 仅在复发时检测到；在 5 名患者中，FLT3/ITD 的长度或数量发生了变化。 FLT3/ITD 的增加可能表明寡克隆性与 FLT3/ITD 阳性克隆的选择性生长有关，而损失可能反映了更成熟的白血病细胞而不是白血病干细胞中的 ITD，或者其他遗传畸变提供了更大的选择优势。在微小残留病环境中研究 FLT3/ITD 动力学可能为我们观察到的变化提供一些答案。 Fms 样酪氨酸激酶 3/ITD 是预后的相关标志物，并且仍然是治疗抑制的重要靶点。
In acute myeloid leukemia (AML), activating mutations in the fms-like tyrosine kinase 3 (FLT3) gene predict poor prognosis. We determined FLT3 internal tandem duplications (FLT3/ITD) and D835 point mutations in paired initial and relapse samples from 80 pediatric and adult AML patients. One D835 point mutation was found in an initial pediatric AML sample. Fms-like tyrosine kinase 3/ITDs were present in 21 initial and 22 relapse samples (26.3 and 27.5%, respectively). Interestingly, FLT3/ITD positivity was related to a significantly shorter time to relapse, most pronounced when the ITD-positive status was found at relapse (P < 0.001). However, FLT3/ITD status changed between diagnosis and relapse in 14 cases. In four patients, the FLT3/ITD became undetectable at relapse in five patients FLT3/ITDs were only detected at relapse, and in five patients the length or number of FLT3/ITDs changed. Gain of FLT3/ITDs may suggest oligoclonality with selective outgrowth of the FLT3/ITD-positive clone, whereas losses may reflect ITDs in the more mature leukemic cells rather than in the leukemic stem cell, or, alternatively, that other genetic aberrations provided a greater selective advantage. Studying FLT3/ITD kinetics in minimal residual disease setting may provide some answers for the changes we observed. Fms-like tyrosine kinase 3/ITD is a relevant marker for prognosis, and remains an important target for therapeutic inhibition.