AML-associated Flt3 kinase domain mutations show signal transduction differences compared with Flt3 ITD mutations
AML-associated Flt3 kinase domain mutations show signal transduction differences compared with Flt3 ITD mutations
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DOI：
10.1182/blood-2004-07-2942
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发表时间：
2005-07-01
期刊：
影响因子：
20.3
通讯作者：
Serve, H
中科院分区：
文献类型：
--
作者：
Choudhary, C;Schwäble, J;Serve, H
Flt 3的激活突变在大约三分之一的急性髓性白血病（AML）患者中发现，是一个有吸引力的药物靶点。Flt 3突变有两类：内膜中的内部串联重复（ITD）和酪氨酸激酶结构域（TKD）中的点突变。我们和其他人已经表明Flt 3-ITD诱导异常信号传导，包括信号转导和转录激活因子5（STAT 5）的强烈激活以及CCAAT/雌二醇结合蛋白α（c/EBP α）和Pu.1的抑制。在这里，我们比较了骨髓祖细胞中Flt 3-ITD与Flt 3-TKD的信号传导特性。我们证明Flt 3-TKD突变诱导32 D细胞在悬浮培养物中自主生长。然而，与Flt 3-ITD相反并且与野生型Flt 3（Flt 3-WT）相似，Flt 3-TKD不能支持半固体培养基中的集落形成。此外，与Flt 3-ITD相反，Flt 3-WT和Fit 3-TKD均不诱导STAT 5靶基因的活化或诱导。Flt 3-TKD也未能抑制c/EBP α和Pu.1。受体自磷酸化以及Erk-1和-2、Akt和Shc的磷酸化没有观察到显着差异。重要的是，TKD而不是ITD突变对酪氨酸激酶抑制剂蛋白激酶C 412（PKC 412）比Flt 3-WT更敏感对数幂。总之，Flt 3-ITD和Flt 3-TKD突变在它们的信号传导特性方面显示出差异，这可能对它们的转化能力和突变特异性治疗方法的设计具有重要意义。
Activating mutations of Flt3 are found in approximately one third of patients with acute myeloid leukemia (AML) and are an attractive drug target. Two classes of Flt3 mutations occur: internal tandem duplications (ITDs) in the juxtamembrane and point mutations in the tyrosine kinase domain (TKD). We and others have shown that Flt3-ITD induced aberrant signaling including strong activation of signal transducer and activator of transcription 5 (STAT5) and repression of CCAAT/estradiol-binding protein alpha (c/EBP alpha) and Pu.1. Here, we compared the signaling properties of Flt3-ITD versus Flt3-TKD in myeloid progenitor cells. We demonstrate that Flt3-TKD mutations induced autonomous growth of 32D cells in suspension cultures. However, in contrast to Flt3-ITD and similar to wild-type Flt3 (Flt3-WT), Flt3-TKD cannot support colony formation in semisolid media. Also, in contrast to Flt3-ITD, neither Flt3-WT nor Fit3-TKD induced activation or induction of STAT5 target genes. Flt3-TKD also failed to repress c/EBP alpha and Pu.1. No significant differences were observed in receptor autophosphorylation and the phosphorylation of Erk-1 and -2, Akt, and Shc. Importantly, TKD but not ITD mutations were a log power more sensitive toward the tyrosine kinase inhibitor protein kinase C 412 (PKC412) than Flt3-WT- In conclusion, Flt3-ITD and Flt3-TKD mutations display differences in their signaling properties that could have important implications for their transforming capacity and for the design of mutation-specific therapeutic approaches.