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

本研究从信号转导、转录调控、细胞周期调控和细胞凋亡等方面分析了造血细胞生长、分化和恶性转化的机制，得到如下结果：1.野生型和致癌型KIT（Asp 814 Val）KIT通过Tyrosine 719激活PI 3-K信号通路诱导细胞生长。2.野生型KIT通过Tyrosine 719和Tyrosine 567激活Src家族酪氨酸激酶和PI 3-K介导趋化性。增强介导细胞生长的Pim-2的表达，同时抑制PU.1和c/EBPa的表达，这两者都诱导粒细胞分化，从而促进未成熟骨髓细胞的生长并抑制其分化。4. Ras、STAT 5和PI 3-K之间的功能合作是BCR/ABL癌基因的完全致癌活性所必需的。5. PML抑制STAT 3活性，而其致癌形式PML/RAR α增强其活性。6.E2F1，G1/S转换的关键调节剂，通过特异性地抑制G1/S转换的NF-κ B活性而使宿主细胞对凋亡敏感。7.我们克隆了一种新的抗凋亡分子Anamorsin，8. Anamorsin基因敲除小鼠在妊娠晚期是胚胎致死性的，这是由于确定性造血

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.