I型和II型CALR基因突变对骨髓增殖性肿瘤微环境影响差异的研究

骨髓增殖性肿瘤（Myeloproliferative Neoplasms, MPN）中CALR基因突变约占30%，CALR突变主要包括I型（52bp缺失）和II型（5bp插入），这两类CALR突变患者的临床症状、疾病预后和转归不同；目前国内外研究主要着眼于基因突变的造血干细胞与MPN的关系，骨髓微环境对MPN表型的形成具有重要作用，而不同突变类型对于骨髓微环境的影响差异研究很少。本项目以已有的研究为基础，利用临床MPN骨髓标本和转基因小鼠模型，研究两类CALR基因突变如何导致不同MPN表型以及骨髓微环境的差异性，阐明不同突变背景下骨髓微环境的差异及何种机制导致不同的疾病表型和预后差异，通过对相关分子信号通路的研究明确导致不同亚型MPN发生的关键分子机制，从微环境角度阐述MPN转归、克隆演变及恶性转化的机制，刻画不同疾病表型下微环境的差异，为该病的靶向治疗和微环境的联合治疗提供理论依据。

The CALR gene mutations, including type I mutation (52 bp deletion) and type II mutation (5 bp insertion), account for about 30% in Myeloproliferative neoplasms (MPN). Patients with type I and type II CALR mutations have different clinical symptoms, disease prognosis and disease outcomes. At present, domestic and international research mainly focuses on the relationship between gene-mutated hematopoietic stem cells and MPN. The bone marrow microenvironment plays an important role in the formation of MPN phenotype, however, studies on the differences in the effects of different mutation types on the bone marrow microenvironment are rare. Based on the existing research, this project uses clinical MPN bone marrow specimens and transgenic mouse models to study how two types of CALR gene mutations lead to different MPN phenotypes, the differences in bone marrow microenvironment, and the mechanism leading to different disease phenotypes and prognosis under different mutation backgrounds. We will try to identify the key molecular mechanisms leading to the occurrence of different subtypes of MPN through the study of related molecular signaling pathways. From the perspective of microenvironment, we will expound the mechanism of MPN progression, clonal evolution and malignant transformation, and characterize the difference of microenvironment under different disease phenotypes, providing a theoretical basis for the targeted therapy of the disease combined with microenvironment.