骨髓微环境紊乱在恶性血液病的发生发展中具有重要作用。急性红白血病（AEL）以红系异常增生为主要特征，发病机制尚不明确。我们前期研究发现AEL患者存在高频GATA2基因突变，且GATA2突变促进了造血干细胞向红系分化；通过基因表达谱发现AEL患者骨髓中肝细胞生长因子（HGF）表达水平下调，且在GATA2突变AEL患者中下调更为显著。造血干细胞单独GATA2突变并不能导致AEL，而HGF是骨髓微环境中维持红系发育的重要细胞因子，我们推测HGF下调协同GATA2突变促进了AEL的发生。本项目拟进一步通过体内外研究，阐明GATA2突变促进红系分化和下调HGF表达的机制；在免疫缺陷小鼠中，研究HGF下调协同GATA2突变在红系异常增生及AEL发生中的作用及机制；建立AEL模型，探讨HGF是否可作为AEL治疗靶点。本研究将部分阐明AEL的发生机制，鉴定潜在的治疗靶点，对AEL的精准诊疗具有重要意义。

Bone marrow microenvironment alterations play a vital role in the genesis and development of hematopoietic malignancies. Acute erythroid leukemia (AEL) is characterized by abnormal erythroid expansion, while the leukemogenesis of AEL remained unknown. Our previous results identified high frequencies of GATA2 mutations in AEL patients and proved that typical GATA2 mutations could promote erythroid differentiation of hematopoietic stem cells (HSC). With microarray we further found that the level of hepatocyte growth factor (HGF) expression was downregulated in AEL patients. Notably, HGF expression was significantly downregulated in GATA2 mutated AEL patients. Given the fact that GATA2 mutations in HSC alone were not able to generate AEL and HGF was the key regulator in erythroid development in the bone marrow microenvironment, we speculated that GATA2 mutations combined with lower HGF could favor AEL genesis. In this study, we are going to explore: 1) the molecular mechanisms of GATA2 mutations in modulating erythroid differentiation and downregulating HGF expression, 2) the synergistic role of HGF and GATA2 mutations in the abnormal erythroid expansion and the leukemogenesis of AEL in the severe immunodeficiency mice, 3) whether HGF could serve as the therapeutic target in AEL model. This project might partially elucidate the leukemogenesis of AEL and identify potential therapeutic targets, which could provide experimental basis of precise diagnostic and treatment strategies of AEL patients.