Transcription factor regulation of malignant cell transformation and its repression

本研究以造血转录因子和白血病为模型系统，研究了转录因子对恶性细胞转化的调控及其抑制作用。GATA-1对于红系和巨核细胞谱系的发育至关重要，在唐氏综合征相关的急性巨核母细胞白血病（AMKL-DS）患者中经常发现导致n端截断形式GATA-1产生的突变。我们发现GATA-1基因敲低的雌性（GATA-1.05/X）小鼠经常出现类似于骨髓增生异常综合征的造血障碍，其特征是祖细胞的积累。我们已经证明GATA-1.05/X小鼠患有两种不同类型的急性白血病。由于GATA-1是一个X染色体基因，因此杂合GATA-1敲低小鼠体内存在两种类型的造血细胞，它们要么携带活跃的野生型GATA-1等位基因，要么携带活跃的突变型GATA-1.05等位基因。在后一种造血祖细胞中，低水平的GATA-1表达足以支持存活，但不能支持分化，从而导致祖细胞的积累，这些祖细胞很容易被致癌刺激靶向。由于在GATA-1-null/X突变小鼠中未观察到此类白血病病例，并且野生型GATA-1的转基因表达使GATA-1.05/X小鼠免于白血病，因此我们得出结论，GATA-1基因敲除小鼠中残留的活性有助于恶性肿瘤的发展。此外，野生型GATA-1能促进AMKL-DS白血病细胞向成熟的红系细胞转变，而截断的GATA-1则不能，提示GATA-1的缺陷是白血病发生的因素之一。

In this study we have studied transcription factor regulation of malignant cell transformation and its repression exploiting hematopoietic transcription factors and leukemia as a model system. GATA-1 is essential for the development of erythroid and megakaryocytic lineages and mutations leading to the production of N-terminus truncated form GATA-1 are frequently found in the Down syndrome-related acute megakaryoblastic leukemia (AMKL-DS) patients. We found that GATA-1 gene knockdown female (GATA-1.05/X) mice frequently develop a hematopoietic disorder that resembles myelodysplastic syndrome characterized by the accumulation of progenitors. We have demonstrated that GATA-1.05/X mice suffer from two distinct types of acute leukemias. Since GATA-1 is an X chromosomal gene, two types of hematopoietic cells reside within heterozygous GATA-1 knockdown mice, bearing either an active wild-type GATA-1 allele or an active mutant GATA-1.05 allele. In the latter hematopoietic progenitors, low-level GATA-1 expression is sufficient to support survival, but not differentiation, leading to the accumulation of progenitors that are easily targeted by oncogenic stimuli. Since such leukemia cases have not been observed in GATA-1-null/X mutant mice and since transgenic expression of wild-type GATA-1 rescue GATA-1.05/X mice from the leukemia, we conclude that the residual GATA-1 activity in the knockdown mice contributes to the development of the malignancy. In addition, wild-type GATA-1 promoted AMKL-DS leukemic cells to mature erythroid cells, but truncated form GATA-1 could not, suggesting that defect of GATA-1 is one of the leukemogenic factors.