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Oncogenic signaling from the hematopoietic growth factor receptors c-Kit and Flt3

机译：造血生长因子受体c-Kit和Flt3的致癌信号

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Signal transduction in response to growth factors is a strictly controlled process with networks of feedback systems, highly selective interactions and finely tuned on-and-off switches. In the context of cancer. detailed signaling studies have resulted in the development of some of the most frequently used means of therapy, with several well established examples such as the small molecule inhibitors imatinib and dasatinib in the treatment of chronic myeloid leukemia. Impaired function of receptor tyrosine kinases is implicated in various types of tumors, and much effort is put into mapping the many interactions and downstream pathways. Here we discuss the hematopoietic growth factor receptors c-Kit and Flt3 and their downstream signaling in normal as well as malignant cells. Both receptors are members of the same family of tyrosine kinases and crucial mediators of stem-and progenitor-cell proliferation and survival in response to ligand stimuli from the surrounding microenvironment. Gain-of-function mutations/alterations render the receptors constitutively and ligand-independently activated, resulting in aberrant signaling which is a crucial driving force in tumorigenesis. Frequently found mutations in c-Kit and Flt3 are point mutations of aspartic acid 816 and 835 respectively, in the activation loop of the kinase domains. Several other point mutations have been identified, but in the case of Flt3, the most common alterations are internal tandem duplications (ITDs) in the juxtamembrane region, reported in approximately 30% of patients with acute myeloid leukemia (AML). During the last couple of years, the increasing understanding of c-Kit and Flt3 signaling has also revealed the complexity of these receptor systems. The impact of gain-of-function mutations of c-Kit and Flt3 in different malignancies is well established and shown to be of clinical relevance in both prognosis and therapy. Many inhibitors of both c-Kit or Flt3 or of their downstream substrates are in clinical trials with encouraging results, and targeted therapy using a combination of such inhibitors is considered a promising approach for future treatments.
机译：响应生长因子的信号转导是一个严格受控的过程，具有反馈系统网络，高度选择性的交互作用以及经过微调的通断开关。在癌症的背景下。详细的信号研究已开发出一些最常用的治疗方法，其中包括一些公认的实例，例如小分子抑制剂伊马替尼和达沙替尼在治疗慢性粒细胞白血病中的作用。受体酪氨酸激酶的功能受损与各种类型的肿瘤有关，并且在绘制许多相互作用和下游途径方面付出了很多努力。在这里，我们讨论了造血生长因子受体c-Kit和Flt3及其在正常细胞和恶性细胞中的下游信号传导。两种受体都是同一酪氨酸激酶家族的成员，并且是干细胞和祖细胞增殖和存活的关键介体，对周围微环境中的配体刺激作出反应。功能获得的突变/改变使受体组成性地和配体非依赖性地激活，导致异常的信号传导，这是肿瘤发生中的关键驱动力。在激酶结构域的激活环中，c-Kit和Flt3中常见的突变分别是天冬氨酸816和835的点突变。还发现了其他几个点突变，但在Flt3的情况下，最常见的改变是近膜区域的内部串联重复（ITD），据报道约30％的急性髓细胞白血病（AML）患者。在最近几年中，对c-Kit和Flt3信号的日益了解也揭示了这些受体系统的复杂性。 c-Kit和Flt3的功能获得性突变在不同恶性肿瘤中的影响已得到充分证实，并且在预后和治疗方面均具有临床意义。 c-Kit或Flt3或其下游底物的许多抑制剂正在临床试验中，并取得令人鼓舞的结果，并且使用此类抑制剂的组合进行靶向治疗被认为是未来治疗的有前途的方法。

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