Lyn is an important component of the signal transduction pathway specific to FLT3/ITD and can be a therapeutic target in the treatment of AML with FLT3/ITD
Lyn is an important component of the signal transduction pathway specific to FLT3/ITD and can be a therapeutic target in the treatment of AML with FLT3/ITD
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DOI：
10.1038/sj.leu.2404547
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发表时间：
2007-03-01
期刊：
影响因子：
11.4
通讯作者：
Naoe, T.
中科院分区：
文献类型：
--
作者：
Okamoto, M.;Hayakawa, F.;Naoe, T.
fms样酪氨酸激酶3 （FLT3）在造血祖细胞中表达。FLT3的内部串联重复（ITD） （FLT3/ITD）是人类成人急性髓性白血病（AML）中最常见的突变。FLT3/ITD有助于FLT3自身及其下游信号组分、丝裂原活化蛋白激酶和转录信号转导及激活因子5 （STAT5）的组成性激活，并使白细胞介素(IL)-3依赖性细胞系能够自主生长。在本研究中，我们发现FLT3/ITD与Lyn的特异性关联，导致Lyn在体内磷酸化。我们还证明了FLT3/ITD受体在体外比野生型FLT3受体对Lyn具有更高的亲和力，并且这种亲和力与受体酪氨酸磷酸化的强度有关。使用靶向Lyn的小干扰RNA （siRNA）和Src家族激酶抑制剂PP2均可抑制表达FLT3/ itd的32D细胞（FLT3/ITD-32D）不依赖il -3的生长，降低Lyn和STAT5的组成磷酸化。PP2处理移植FLT3/ITD-32D细胞的小鼠可以阻断肿瘤的发生，减小已形成的肿瘤的大小。这些结果表明Lyn是FLT3/ITD特异性信号转导通路的重要组成部分，可以作为FLT3/ITD治疗AML的治疗靶点。
Fms-like tyrosine kinase 3 (FLT3) is expressed in hematopoietic progenitor cells. An internal tandem duplication (ITD) of FLT3 (FLT3/ITD) is the most frequent mutation in human adult acute myeloid leukemia (AML). FLT3/ITD contributes to the constitutive activation of FLT3 itself and its downstream signal components, mitogen-activated protein kinase and signal transducers and activators of transcription 5 (STAT5), and enables interleukin (IL)-3-dependent cell lines to grow autonomously. In the present study, we showed the specific association of FLT3/ITD with Lyn, which led to the phosphorylation of Lyn in vivo. We also demonstrated that FLT3/ITD receptors displayed a higher affinity to bind to Lyn than wild-type FLT3 receptors in vitro and that this affinity was relative to the intensity of tyrosil phosphorylation of the receptor. Both treatment with small interfering RNA ( siRNA) targeting Lyn and the Src family kinase inhibitor PP2 suppressed the IL-3-independent growth of FLT3/ITD-expressing 32D cells (FLT3/ITD-32D), reducing the constitutive phosphorylation of Lyn and STAT5. PP2 treatment of mice transplanted with FLT3/ITD-32D cells blocked the onset of tumors and decreased the size of established tumors. These results demonstrate that Lyn is an important component of the signal transduction pathway specific to FLT3/ITD and can be a therapeutic target in the treatment of AML with FLT3/ITD.