Internal tandem duplication of FLT3 (FLT3/ITD) induces increased ROS production, DNA damage, and misrepair: implications for poor prognosis in AML
Internal tandem duplication of FLT3 (FLT3/ITD) induces increased ROS production, DNA damage, and misrepair: implications for poor prognosis in AML
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DOI：
10.1182/blood-2007-05-092510
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发表时间：
2008-03-15
期刊：
影响因子：
20.3
通讯作者：
Rassool, Feyruz
中科院分区：
文献类型：
--
作者：
Sallmyr, Annahita;Fan, Jinshui;Rassool, Feyruz
fms样酪氨酸激酶-3 （FLT3）受体的激活突变发生在大约30%的急性髓性白血病（AML）患者中，至少对于内部串联重复（ITD）突变，与预后不良有关。FLT3突变触发下游信号通路，包括RAS-MAP/AKT激酶和信号换能器和转录激活因子-5 （STAT5）。我们发现FLT3/ITD突变启动了基因组不稳定循环，由此增加的活性氧（ROS）产生导致DNA双链断裂（DSBs）增加和修复错误，这可能解释了FLT3/ITD患者侵袭性AML的原因。转染FLT3/ITD和FLT3/ITD阳性的AML细胞系和原代细胞显示ROS增加。增加的ROS水平似乎是通过STAT5信号和RAC1的激活产生的，RAC1是产生ROS的NADPH氧化酶的重要组成部分。RAC1-GTP与磷酸化STAT5 （pSTAT5）的直接结合为ROS的产生提供了可能的机制。FLT3抑制剂阻断FLT3/ITD细胞中增加的ROS，从而降低DSB，提高修复效率和保真度。我们的研究表明，FLT3/ITD突变AML患者的疾病侵袭性和不良预后可能是由内源性ROS升高、DNA损伤增加和末端连接保真度降低驱动的基因组不稳定性增加的结果。
Activating mutations of the FMS-like tyrosine kinase-3 (FLT3) receptor occur in approximately 30% of acute myeloid leukemia (AML) patients and, at least for internal tandem duplication (ITD) mutations, are associated with poor prognosis. FLT3 mutations trigger downstream signaling pathways including RAS-MAP/AKT kinases and signal transducer and activator of transcription-5 (STAT5). We find that FLT3/ITD mutations start a cycle of genomic instability whereby increased reactive oxygen species (ROS) production leads to increased DNA double-strand breaks (DSBs) and repair errors that may explain aggressive AML in FLT3/ITD patients. Cell lines transfected with FLT3/ITD and FLT3/ITD-positive AML cell lines and primary cells demonstrate increased ROS. Increased ROS levels appear to be produced via STAT5 signaling and activation of RAC1, an essential component of ROS-producing NADPH oxidases. A direct association of RAC1-GTP binding to phosphorylated STAT5 (pSTAT5) provides a possible mechanism for ROS generation. A FLT3 inhibitor blocked increased ROS in FLT3/ITD cells resulting in decreased DSB and increased repair efficiency and fidelity. Our study suggests that the aggressiveness of the disease and poor prognosis of AML patients with FLT3/ITD mutations could be the result of increased genomic instability that is driven by higher endogenous ROS, increased DNA damage, and decreased end-joining fidelity.