NOX4-driven ROS formation mediates PTP inactivation and cell transformation in FLT3ITD-positive AML cells
NOX4-driven ROS formation mediates PTP inactivation and cell transformation in FLT3ITD-positive AML cells
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DOI：
10.1038/leu.2015.234
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发表时间：
2016-02-01
期刊：
影响因子：
11.4
通讯作者：
Boehmer, F-D
中科院分区：
文献类型：
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作者：
Jayavelu, A. K.;Mueller, J. P.;Boehmer, F-D
FMS样酪氨酸激酶3（FLT 3）的激活突变，特别是内部串联重复（ITD），与急性髓性白血病（AML）的严重预后相关。转化FLT 3 ITD信号转导导致活性氧（ROS）的形成和蛋白酪氨酸磷酸酶（PTP）DEP-1/PTPRJ（FLT 3信号转导的负调节因子）的失活。在这里，我们讨论了潜在的机制和生物学后果。发现NADPH氧化酶4（NOX 4）信使RNA和蛋白质表达在FLT 3 ITD阳性细胞中升高，并依赖于FLT 3 ITD信号传导和STAT 5介导的NOX 4启动子激活。NOX 4敲低降低了ROS水平，恢复了DEP-1 PTP活性，并减弱了FLT 3 ITD驱动的转化。此外，Nox 4敲除（Nox 4（-/-））小鼠造血祖细胞在体外FLT 3 ITD介导的转化难治。在C3 H/HeJ小鼠中由FLT 3 ITD转化的32 D细胞引起的骨髓增殖样疾病（MPD）的发展，以及在用MLL-AF 9/FLT 3 ITD转化的鼠造血干细胞移植的小鼠中白血病样疾病的发展通过N 0X 4下调而强烈减弱。发现N 0X 4靶向化合物抵消小鼠中FLT 3 ITD阳性AML母细胞的增殖和MPD发展。这些发现揭示了一种以前未被认识到的癌蛋白驱动的PTP氧化机制，并表明干扰FLT 3 ITD-STAT 5-NOX 4介导的ROS过度产生和PTP失活可能在AML亚组中具有治疗潜力。
Activating mutations of FMS-like tyrosine kinase 3 (FLT3), notably internal tandem duplications (ITDs), are associated with a grave prognosis in acute myeloid leukemia (AML). Transforming FLT3ITD signal transduction causes formation of reactive oxygen species (ROS) and inactivation of the protein-tyrosine phosphatase (PTP) DEP-1/PTPRJ, a negative regulator of FLT3 signaling. Here we addressed the underlying mechanisms and biological consequences. NADPH oxidase 4 (NOX4) messenger RNA and protein expression was found to be elevated in FLT3ITD-positive cells and to depend on FLT3ITD signaling and STAT5-mediated activation of the NOX4 promoter. NOX4 knockdown reduced ROS levels, restored DEP-1 PTP activity and attenuated FLT3ITD-driven transformation. Moreover, Nox4 knockout (Nox4(-/-)) murine hematopoietic progenitor cells were refractory to FLT3ITD-mediated transformation in vitro. Development of a myeloproliferative-like disease (MPD) caused by FLT3ITD-transformed 32D cells in C3H/HeJ mice, and of a leukemia-like disease in mice transplanted with MLL-AF9/ FLT3ITD-transformed murine hematopoietic stem cells were strongly attenuated by NOX4 downregulation. NOX4-targeting compounds were found to counteract proliferation of FLT3ITD-positive AML blasts and MPD development in mice. These findings reveal a previously unrecognized mechanism of oncoprotein-driven PTP oxidation, and suggest that interference with FLT3ITD-STAT5-NOX4-mediated overproduction of ROS and PTP inactivation may have therapeutic potential in a subset of AML.