TET2异常间充质干细胞调控造血及血液髓系肿瘤的作用及相关机制研究

Mesenchymal stem cell (MSC) plays an important role in the proliferation and differentiation of hematopoietic stem cell (HSC), and the infiltration and prognosis of hematopoietic myeloid malignancies. TET2 are methylcytosine dioxygenases that regulate cytosine hydroxymethylation. TET2 mutation is essential and critical for the pathogenesis and prognosis of myeloid malignancy. Our previous results demonstrated that TET2 dysregulation was detected in MSC derived from patients with myeloid malignancies. In addition, TET2-dysregulation MSC could change the state of DNA methylation and modulate gene transcription, which paly an important role in the pathogenesis and prognosis of myeloid malignancies. These findings provide a framework for further studies. First, we will check the expression and mutation of TET2 in MSC derived from patients with myeloid malignancies. Moreover, the biological characteristics of TET2-dysregulation MSC will be studied. Second, we will study the role and mechanism of TET2-dysregulation MSC in the regulation of hematopoiesis and hematopoietic myeloid malignancies. Last, the function of TET2-dysregulation MSC on the prognosis of myeloid malignancies with different mutation will be studied using mouse transplantation model. Advances in our knowledge of the function of TET2-dysregulation MSC on hematopoiesis, coupled with an improved understanding of the role and mechanism of TET2-dysregulation MSC on the progression and prognosis of myeloid malignancies, will probably lead to the development of additional therapies and multivariate risk classification that improve outcomes for patients with myeloid malignancies.

间充质干细胞（MSC）在造血干细胞增殖、分化和血液髓系肿瘤侵袭和预后中发挥重要作用。TET2是体内调控DNA甲基化最重要的蛋白酶，其异常是血液髓系肿瘤重要的发病及预后因素。我们前期实验发现血液髓系肿瘤患者骨髓MSC存在TET2表达异常，TET2异常MSC通过改变甲基化状态调控关键基因的表达，进而影响血液髓系肿瘤的进展和预后。本课题拟在前期实验基础上，进行如下研究: ①详述血液髓系肿瘤患者骨髓MSC中TET2表达情况及TET2异常MSC的生物学特性；②探寻TET2异常MSC影响造血及调控血液髓系肿瘤的功能和具体机制；③通过动物移植实验阐明TET2异常MSC调控血液髓系肿瘤预后的作用。本研究通过探索TET2异常MSC发挥调控造血的作用和机制，阐明其在血液髓系肿瘤进展和预后中的作用及机制，建立包括骨髓MSC在内的血液髓系肿瘤分子标志物预后分层新模式，为血液髓系肿瘤的精准治疗提供新的治疗靶点。

间充质干细胞(MSC)在造血干细胞增殖、分化和血液髓系肿瘤侵袭和预后中发挥重 要作用。TET2是体内调控DNA甲基化最重要的蛋白酶，其异常是血液髓系肿瘤重要的发病 及预后因素。我们前期实验发现血液髓系肿瘤患者骨髓MSC存在TET2表达异常，TET2异常M SC通过改变甲基化状态调控关键基因的表达，进而影响血液髓系肿瘤的进展和预后。本课 题拟在前期实验基础上，进行如下研究: 1详述血液髓系肿瘤患者骨髓MSC中TET2表达情 况及TET2异常MSC的生物学特性;2探寻TET2异常MSC影响造血及调控血液髓系肿瘤的功能 和具体机制;3通过动物移植实验阐明TET2异常MSC调控血液髓系肿瘤预后的作用。本研 究通过探索TET2异常MSC发挥调控造血的作用和机制，阐明其在血液髓系肿瘤进展和预后 中的作用及机制，建立包括骨髓MSC在内的血液髓系肿瘤分子标志物预后分层新模式，为 血液髓系肿瘤的精准治疗提供新的治疗靶点。