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A study of growth mechanism of leukemic blast progenitors in AML.

AML中白血病原始细胞生长机制的研究。

基本信息

批准号：
04671535
负责人：
MUROHASHI Ikuo
金额：
$ 1.28万
依托单位：
Saitama Medical School
依托单位国家：
日本
项目类别：
Grant-in-Aid for General Scientific Research (C)
财政年份：
1992
资助国家：
日本
起止时间：
1992 至 1993
项目状态：
已结题

来源：
https://kaken.nii.ac.jp/en/grant/KAKENHI-PROJECT-04671535/
关键词：
Leukemic blast progenitors AML TGF-beta1 TNF-alpha TGF-beta_1 TNF-alpha TGF-β

项目摘要

The growth of leukemic blast progenitors from AML patients is under the control of complex network of cytokines. Among cytokines produced by AML blasts and stimulate the growth of their own progenitors, TNF-a possess most powerful effect. We investigated the effects of various cytokines on the growth of leukemic blast progenitors and expression of proto-oncogenes, induction of apoptosis, and cell cycle of blasts.1. Role of TGF-b1. TGF-b1 did not affect the growth of G-CSF supported normal hematopoietic progenitors, but suppressed the one supported by GM-CSF, IL-3, or SCF, and the suppression by TGF-b1 was increased in this order. TGF-b1 profoundly suppressed the growth of leukemic blast progenitors, irrespective of growth factor used. By experiments with c-Myc and c-Myb antisense oligonucleotides and Northern blot analysis, c-Myc and c-Myb may be directly related to TGF-b1 suppression. In normal hematopoietic progenitors, TGF-b1 preferentially suppressed the primitive ones. In hematolo … More gic malignancies, TGF-b1 suppression was increased with progression of clonal evolution, and may be related to the activation of endogenous tyrosine kinase activity. TGF-b1 inhibited the expression of c-kit and Fas mRNA by AML blasts, and seems to act against apoptosis and differentiation.2. Role of TNF-a. TNF-a alone enhanced the transition of AML blasts to S phase, but failed to stimulate the growth of leukemic blast progenitors. In the presence of cytokine such as IL-3, TNF-a powerfully stimulated the clonogenic cell growth. TNF-a stimulated the expression of c-kit, c-jun, and Fas mRNA by blasts, and induced differentiation of the cells. TGF-b1 almost completely abolished growth stimulating effect of TNF-a.Induction of apoptosis of AML blasts. When AMl blasts were cultured in vitro in the absence of growth factor, expression of c-jun and c-fos mRNA, transition into S phase, and induction of apoptosis of the cells were observed. Addition of factor such as IL-3 prevented apoptosis and suppressed c-jun transcript and enhanced c-fos transcript. In some AML cases, cells remained in G0/G1 phase, and did not express c-jun and c-fos mRNA, and apoptosis was not observed. The proportion of c-Jun/c-Fos may play an importent role in induction of apoptosis of AML blasts. Less

AML患者的白血病原始祖细胞的生长受到复杂的细胞因子网络的控制。在由AML原始细胞产生并刺激其自身祖细胞生长的细胞因子中，TNF-α具有最强的作用。我们研究了各种细胞因子对白血病原始祖细胞生长、原癌基因表达、细胞凋亡诱导和细胞周期的影响. TGF-β 1的作用TGF-β 1对G-CSF支持的正常造血祖细胞的生长无影响，但对GM-CSF、IL-3、SCF支持的正常造血祖细胞的生长有抑制作用，且抑制作用依次增强。TGF-β 1深刻地抑制白血病原始祖细胞的生长，无论使用的生长因子。通过c-Myc和c-Myb反义寡核苷酸实验和北方印迹分析，c-Myc和c-Myb可能与TGF-β 1抑制直接相关。在正常造血祖细胞中，TGF-β 1优先抑制原始造血祖细胞。因赫莫罗 ...更多信息在恶性肿瘤中，TGF-β 1抑制随着克隆进化的进展而增加，并且可能与内源性酪氨酸激酶活性的激活有关。结论：1. TGF-β 1抑制AML母细胞c-kit和Fas mRNA的表达，可能具有抗凋亡和抗分化作用. TNF-a的作用单独TNF-α促进AML母细胞向S期的转变，但不能刺激白血病母细胞祖细胞的生长。在细胞因子如IL-3的存在下，TNF-α强烈地刺激克隆形成细胞的生长。TNF-α刺激原始细胞表达c-kit、c-jun和Fas mRNA，诱导细胞分化。TGF-β_1几乎完全阻断TNF-α的促生长作用。诱导AML母细胞凋亡。在无生长因子的条件下体外培养AM 1细胞，观察到c-jun和c-fos mRNA的表达，细胞进入S期，并诱导细胞凋亡。加入IL-3等因子可抑制细胞凋亡，抑制c-jun转录，增强c-fos转录。部分AML细胞仍停留在G 0/G1期，不表达c-jun和c-fos mRNA，未观察到细胞凋亡。c-Jun/c-Fos的比例可能在诱导AML细胞凋亡中起重要作用。少