NF1在髓系肿瘤发病中的作用研究

髓系肿瘤是一大类造血系统恶性克隆性疾病，其临床表现多样，但发病往往涉及一系列共同的信号通路、转录因子或表观遗传调节分子异常。神经纤维瘤I型基因(Neurofibromatosis type 1, NF1)就是其中一个重要的肿瘤抑制基因，其编码产物能够负性调节Ras活性。NF1突变与AML、MDS/MPN、MPN等髓系肿瘤的发生关系密切。以往研究大多集中在造血细胞中NF1的改变对疾病的影响，而造血微环境中NF1的作用尚未明确。我们前期研究发现NF1表达下调同时出现在髓系肿瘤细胞和其微环境的间充质干细胞中，由此推测NF1异常的造血细胞及微环境可能共同参与了髓系肿瘤的发病。本研究将从患者生物样本分析、细胞生物学功能/分子机制研究和小鼠模型等多方面出发，探索NF1异常致病过程中的造血细胞与微环境之间的相互作用及分子机制，从整体上揭示NF1介导的髓系肿瘤发病作用规律，为靶向NF1治疗提供理论依据。

Myeloid malignancies are a class of clonal hematopoietic disorders with varied clinical features, however, a series of mutual gene mutations including signaling pathways, transcription factors and epigenetic regulators are involved, and one of these genes is Neurofibromatosis type 1 (NF1). NF1 acts as a tumor suppressor gene by encoding neurofibromin that negatively regulates the biochemical activation of Ras. Mutation of NF1 was closely related to the occurrence of myeloid malignancies including acute myeloid leukemia (AML), myelodysplastic/myeloproliferative neoplasm (MDS/MPN), as well as myeloproliferative neoplasm (MPN). Most of the previous studies of NF1 were focused on the effects of genotype change in malignant hematopoietic cells. However, the effects of NF1 in hematopoietic microenvironment cells are not clearly delineated. Our previous work showed that the suppressed expression of NF1 was identified not only in the hematopoietic cells of patients with myeloid malignancies, but also in the mesenchymal stem cells, known as a major marrow niche component. Therefore, we hypothesize that dysregulation of NF1 in both hematopoietic and mesenchymal systems are involved in the pathogenesis of myeloid malignancies. In this proposal, we will analyze the effects of NF1 inactivation on multiple levels, including phenotypic analysis of clinical specimens, in vitro cellular function/molecular mechanism studies, as well as mouse model in vivo, to elucidate the interaction and intrinsic mechanism between hematopoietic and mesenchymal systems with dysregulated NF1. By exploring the role of NF1 in the pathogenesis of different types of myeloid malignancies, this study will provide further insight for NF1 targeting therapy in myeloid malignancies.