截短型HLA-I类分子在髓系血液肿瘤发生发展中的作用

Immune, especially immune surveillance, plays an important role in hematological malignancies initiation and progress. HLA-I molecule presents antigen in the immune response, and plays an important role in immune surveillance of tumor cells. HLA molecular mutations are barely investigated in hematological malignancies initiation and progress. We firstly found truncated HLA-I mutations from myeloid hematological malignancies. We have obtained GenBank accession numbers. We plan to investigate it further in this project: ①To elucidate the incidence and distribution of HLA-I mutation in myeloid hematological malignancies; ②To investigate the.expression and location of the truncated HLA-I molecule; ③To investigate the effect of truncated HLA-I molecule in antigen presentation in target cells; ④To investigate the effect of truncated HLA-I molecule in antigen presentation in antigen-presenting cells; ⑤To investigate the effects of soluble truncated HLA-I molecule in CTL and NK cells proliferation, apoptosis and cytotoxicity; ⑥To investigate the effect of truncated HLA-I molecule on immune surveillance in mice. We are going to explore the effects of truncated HLA-I molecule in immune response, especially in immune surveillance of myeloid hematological malignancies. This project will uncover the role of immune abnormalities related to HLA-I mutation in myeloid hematological malignancies initiation and progress.

免疫异常尤其免疫监视异常在肿瘤的发生发展中具有重要作用。HLA-I类分子在免疫反应中参与抗原递呈，在肿瘤免疫监视中具有重要作用。HLA-I类分子突变在髓系血液肿瘤中的作用鲜有研究。申请者在3例髓系血液肿瘤患者发现截短型HLA-I类分子突变，均已获得GenBank登录号。在此基础上，本项目拟研究①HLA-I类分子突变在髓系血液肿瘤中的发生率和病种分布②截短型HLA-I类分子的细胞表达和定位③截短型HLA-I类分子对靶细胞抗原递呈的影响④截短型HLA-I类分子对抗原递呈细胞抗原递呈的影响⑤截短型HLA-I类分子作为可溶性HLA分子对CTL和NK细胞增殖、凋亡及杀伤功能的影响⑥通过小鼠体内实验，研究截短型HLA-I类分子对髓系血液肿瘤细胞免疫监视的影响。通过本项目探讨截短型HLA-I类分子突变对免疫功能的影响及机制，阐明截短型HLA-I类分子突变在髓系血液肿瘤发生发展中的作用。

免疫异常尤其免疫监视异常在肿瘤的发生发展中具有重要作用。申请者在3例髓系血液肿瘤患者发现截短型HLA-I类分子突变，在此基础上，本项目研究了①HLA-I类分子突变在髓系血液肿瘤中的发生率和病种分布。通过检测1038例血液肿瘤（包括白血病、骨髓增殖性肿瘤、骨髓增生异常综合症等）的HLA-I类分子的DNA序列，我们发现一例AML-M5男性患者出现HLA-B*40:01:02:01位点的EXON3点突变，K178X，形成终止密码子，故HLA-I类分子突变在血液肿瘤中的发生率低于千分之一。②根据前期已发现的3例患者的序列，构建3个野生型HLA质粒（pcDNA.3.1/myc-His(-)A-HLA-A2.6、pcDNA.3.1/myc-His(-)A-HLA-B13.2、pcDNA.3.1/myc-His(-)A-HLA-B40.2）和3个截短型HLA质粒（pcDNA.3.1/myc-His(-)A-HLA-A2.6-truncated、pcDNA.3.1/myc-His(-)A-HLA-B13.2-truncated、pcDNA.3.1/myc-His(-)A-HLA-B40.2-truncated），并测序确认。③把这6个HLA质粒转染K562细胞系，检测HLA-A和HLA-B的mRNA水平。用Anti-6X His tag抗体、Anti-HLA A抗体和Anti-HLA B抗体检测转染K562的蛋白表达。用免疫荧光检测了HLA-A和HLA-B在转染K562细胞系中的表达情况。阐明截短型HLA-I类分子突变在髓系血液肿瘤发生发展中的作用。.发表SCI文章6篇，总影响因子14.793分，中文核心期刊3篇。