FAM122A抑制红细胞分化及分子机制研究

GATA1是调控红系终末分化阶段的关键转录因子，其异常调变参与红系发育分化疾病的发生发展，是该领域的研究热点。FAM122A是进化上高度保守但功能尚不明确的蛋白质。本课题组曾报道它是蛋白磷酸酶2A的内源性抑制分子，近年来发现它在维持肝细胞癌细胞和急性髓系白血病细胞的生长中发挥不可或缺的作用。通过BioGPS数据库，我们发现FAM122A在人源CD71阳性的早期红细胞发育阶段表达显著增高，提示其可能参与红系分化过程。通过人原代CD34阳性细胞和红白血病细胞的体外诱导分化模型，我们发现FAM122A在红系终末分化阶段表达下调，并能够显著抑制红细胞分化诱导效应，该抑制效应很可能通过抑制GATA1的DNA结合和转录活性而实现。本课题将以此为基础，在进一步确认FAM122A调控红系分化的基础上，从分子、细胞、条件性敲除小鼠和临床样本等不同层面深入探讨FAM122A抑制红系分化分子机制及病理生理意义。

GATA1 is a key transcription factor in the regulation of terminal erythrocytic differentiation, and its abnormal regulation is closely related to the occurrence and development of erythroid differentiation-related diseases, which is a research hotspot in this field. FAM122A is a highly conserved but poorly understood protein. Our group reported previously that it is an endogenous inhibitor of protein phosphatase 2A. In recent years, we have found that FAM122A plays an indispensable role in maintaining the growth of hepatocellular carcinoma cells and acute myeloid leukemia cells. Through the BioGPS database, we found that FAM122A is significantly upregulated in CD71 positive erythroid cells (the early stage of erythroid development), suggesting that FAM122A may participate in the process of erythroid differentiation. Through the in vitro differentiation induction model of human primary CD34 positive and erythroleukemic cells, we found that FAM122A is down-regulated in terminal erythroid differentiation, and can significantly inhibit the differentiation induction, which is possibly through the inhibition of DNA binding and transcriptional activity of GATA1, an important transcription factor in erythroid differentiation. Based on this, we will further confirm the role of FAM122A in the regulation of erythroid differentiation, and explore the molecular mechanism and pathophysiological significance of FAM122A-inhibiting erythroid differentiation from different levels including molecules, cells, conditional knockout mice and clinical samples.