Institute of Infection, Immunity and Inflammation, Level 3, Glasgow Biomedical Research Centre, 120, University Place, Glasgow, G12 8TA, UK.
J Hematol Oncol. 2012 Aug 1;5:45. doi: 10.1186/1756-8722-5-45.
Although GATA1 is one of the most extensively studied haematopoietic transcription factors little is currently known about the physiological functions of its naturally occurring isoforms GATA1s and GATA1FL in humans-particularly whether the isoforms have distinct roles in different lineages and whether they have non-redundant roles in haematopoietic differentiation. As well as being of general interest to understanding of haematopoiesis, GATA1 isoform biology is important for children with Down syndrome associated acute megakaryoblastic leukaemia (DS-AMKL) where GATA1FL mutations are an essential driver for disease pathogenesis.
Human primary cells and cell lines were analyzed using GATA1 isoform specific PCR. K562 cells expressing GATA1s or GATA1FL transgenes were used to model the effects of the two isoforms on in vitro haematopoietic differentiation.
We found no evidence for lineage specific use of GATA1 isoforms; however GATA1s transcripts, but not GATA1FL transcripts, are down-regulated during in vitro induction of terminal megakaryocytic and erythroid differentiation in the cell line K562. In addition, transgenic K562-GATA1s and K562-GATA1FL cells have distinct gene expression profiles both in steady state and during terminal erythroid differentiation, with GATA1s expression characterised by lack of repression of MYB, CCND2 and SKI.
These findings support the theory that the GATA1s isoform plays a role in the maintenance of proliferative multipotent megakaryocyte-erythroid precursor cells and must be down-regulated prior to terminal differentiation. In addition our data suggest that SKI may be a potential therapeutic target for the treatment of children with DS-AMKL.
尽管 GATA1 是研究最为广泛的造血转录因子之一，但目前人们对其天然存在的同工型 GATA1s 和 GATA1FL 在人类中的生理功能知之甚少——特别是同工型是否在不同谱系中具有不同的作用，以及它们在造血分化中是否具有非冗余的作用。除了对理解造血具有普遍意义外，GATA1 同工型生物学对于患有唐氏综合征相关急性巨核细胞白血病（DS-AMKL）的儿童也很重要，因为 GATA1FL 突变是疾病发病机制的一个重要驱动因素。
使用 GATA1 同工型特异性 PCR 分析人原代细胞和细胞系。使用表达 GATA1s 或 GATA1FL 转基因的 K562 细胞来模拟两种同工型对体外造血分化的影响。
我们没有发现 GATA1 同工型具有谱系特异性使用的证据；然而，在细胞系 K562 中体外诱导终末巨核细胞和红细胞分化时，GATA1s 转录本而不是 GATA1FL 转录本下调。此外，转基因 K562-GATA1s 和 K562-GATA1FL 细胞在稳态和终末红细胞分化过程中具有不同的基因表达谱，GATA1s 表达的特征是缺乏对 MYB、CCND2 和 SKI 的抑制。
这些发现支持 GATA1s 同工型在维持增殖性多能巨核细胞-红细胞前体细胞中的作用的理论，并且在终末分化之前必须下调。此外，我们的数据表明 SKI 可能是治疗患有 DS-AMKL 的儿童的潜在治疗靶点。
