Analysis on the mechanism of survival, growth and differentiation of hematopoietic cells

本研究从信号转导、转录调控、细胞周期调控和凋亡等方面分析了造血细胞的生长、分化和恶性转化的机制，得到如下结果：1.造血细胞的生长、分化和恶性转化的机制。野生型KIT和致癌型（Asp814Val） KIT均通过酪氨酸719.2激活PI3-K信号通路诱导细胞生长。野生型KIT通过Tyrosine719和Tyrosine567.3激活Src家族酪氨酸激酶和PI3-K介导趋化作用。含有ITD的致癌FLT3可增强介导细胞生长的Pim-2的表达，同时抑制诱导粒细胞分化的PU.1和c/EBPa的表达，从而促进未成熟髓细胞的生长，抑制其分化。Ras、STAT5和PI3-K三者之间的功能协同是BCR/ABL癌基因充分发挥致瘤活性的必要条件。PML抑制STAT3活性，而其致癌形式PML/RARa则增强其活性。E2F1是Gl/S转变的关键调节因子，通过特异性抑制NF-kB活性使宿主细胞对Gl/S转变敏感。我们克隆了一个新的抗凋亡分子Anamorsin，它与已知的凋亡相关分子没有同源性。由于最终造血功能的缺陷，Anamorsin基因敲除小鼠在妊娠后期是胚胎致死的。

In this study, we have analyzed the mechanisms of growth, differentiation and malignant transformation of hematopoietic cells from the aspects of signal transduction, transcriptional regulation, cell cycle regulation and apoptosis and got the results as follows :1.Both wild-type KIT and oncogenic (Asp814Val) KIT induce cell growth by activating PI3-K signal pathway through Tyrosine719.2.Wild type KIT mediates chemotaxis by activating Src family tyrosine kinases and PI3-K through Tyrosine719 and Tyrosine567.3.Oncogenic FLT3 containing the internal tandem duplication (ITD) enhances the expression of Pim-2 that mediates cell growth, while it suppresses that of PU.1 and c/EBPa, both of which induce granulocytic differentiation, thereby enhancing the growth and inhibiting the differentiation of immature myeloid cells.4.Functional cooperation among Ras, STAT5, and PI3-K is required for full oncogenic activity of BCR/ABL oncogene.5.PML inhibits STAT3 activity, while its oncogenic form PML/RARa enhances its activity.6.E2F1, a critical regulator of Gl/S transition, sensitizes host cells to apoptosis by inhibiting NF-kB activity specifically at Gl/S transition.7.We have cloned a novel anti-apoptotic molecule Anamorsin, which reveals no homology to known apoptosis related molecules.8.Knockout mice for Anamorsin are embryonic lethal at late gestation due to the defect of definitive hematopoiesis.