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对于红系和巨核系的发育是必不可少的，在唐氏综合征相关的急性巨核细胞白血病(AMKL-DS)患者中经常发现突变导致N端截短型GATA-1的产生。我们发现，GATA-1基因敲除雌性(GATA-1.05/X)小鼠经常发生类似骨髓增生异常综合征的造血障碍，其特征是祖细胞聚集。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，在杂合的GATA-1基因敲除小鼠体内存在两种类型的造血细胞，携带活跃的野生型GATA-1等位基因和活跃的突变型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，导致容易被致癌刺激靶向的造血祖细胞的积累。由于在GATA-1缺失/X突变小鼠中没有观察到这种白血病病例，而且由于野生型GATA-1转基因表达将GATA-1.05/X小鼠从白血病中拯救出来，我们得出结论，GATA-1基因敲除小鼠中残留的GATA-1活性参与了肿瘤的发展。此外，野生型GATA-1可促进AMKL-DS白血病细胞向成熟红系细胞分化，而截短型GATA-1则不能，提示GATA-1缺陷是导致白血病的因素之一。

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.