Analysis of leukemogenesis caused by disruption of gene regulatory mechanisms mediated by multiple transactivation domains

GATA 1是一种转录因子，利用分别位于分子氨基（N）和羧基（C）末端的两个独立的反式激活结构域（TADs），对参与红系/巨核细胞分化的基因进行全面调控。唐氏综合征患儿的急性巨核细胞白血病（AMKL）与GATA 1缺乏N-Arg相关。我们建立了转基因小鼠品系，表达突变GATA 1 s缺乏N-binding或C-binding，并分析了在小鼠中的域的功能。我们发现，N-羟脯氨酸和C-羟脯氨酸对胎儿造血都很重要。我们还发现，在红系细胞中，由于缺乏一个N-bu而引起的功能紊乱可以通过其他N-bu的功能增强来补偿，而在巨核细胞中，N-bu功能的缺乏不能得到补偿。这些结果表明，一个偏反式激活活动所造成的单一功能的C-β参与唐氏综合征AMKL的发病。

GATA1 is a transcription factor essential for comprehensive regulation of genes involved in erythroid/megakaryocytic cell differentiation, utilizing two separate transactivation domains (TADs) located in amino(N)- and carboxyl(C)-terminal region of the molecule, respectively. Acute megakaryoblastic leukemia (AMKL) in children with Down syndrome is associated with GATA1 lacking N-TAD. We established transgenic mouse lines expressing mutant GATA1s lacking either N-TAD or C-TAD and analyzed the function of the domains in mice. We found that both N-TAD and C-TAD are important for fetal hematopoiesis. We also found that the disturbed function due to the lack of one TAD could be compensated by the functional enhancement of the other TAD in erythroid cells, whereas lack of N-TAD function could not be compensated in megakaryocytes. These results indicate that a skewed transactivation activity caused by single function of C-TAD is involved in the onset of Down syndrome AMKL.