骨髓增生异常综合征和骨髓增殖性肿瘤合并骨髓纤维化作用机制研究

MPN and MDS are chronic clonal disorders which arise from defective hematopoietic stem cells (HSCs) and progenitor cells (HPCs).BM fibrosis is often observed in patients with MPN or MDS and is associated with poor prognosis. Our preliminary data showed that, in our Mll-PTD/ m RUNX1 mouse model, the expression level of hypoxia-inducible factor 1α (HIF-1α) protein and mRNA of HIF-1α target genes were significantly up-regulated compared with control mice. However, it is unknown that whether Jak2 V617 F is synergized with HIF-1α to contribute to BM fibrosis. Thus, we propose our central hypothesis: HIF-1α mediated inflammatory immune response, lineage skewing, and abnormal cytokine production play critical roles for BM fibrosis development in MPN and MDS. Based upon our hypothesis, we postulate uncover of common mechanism for BM fibrosis to be an effective treatment strategy for these diseases.Try to determine the key inflammatory lineage(s)inHIF-1α mediated BM fibrosis, determine the significance role of HIF-1α in JAK2 V617F mediated BM fibrosis and determine the significance and the source of TGF-β1(hematopoietic cells and BM stromal cells) in BM fibrosis.These results could make considerable progress in understanding about the common mechanism for BM fibrosis in MPN and MDS, leading to new targeted treatments with reduced toxicity and increased survival rates, for a significant population of MPNand MDS patients who have yet to benefit from targeted therapies.

MPN和MDS都是起源于有缺陷的造血干细胞/祖细胞的慢性克隆性疾病。在MPN或MDS患者中常伴有骨髓纤维化，预后不良。我们前期在MLL-PTD/mRUNX1- MDS小鼠模型研究中发现，HIF-1α及其下游靶基因激活，与MDS合并骨髓纤维化密切相关；在Jak2 V617F 鼠模型中， Jak2 V617F是否与HIF-1α共同作用导致骨髓纤维化机制尚不明确。因此，我们提出本课题，通过基因工程的方法在不同血细胞中诱导HIF-1α表达，从而确定HIF-1α介导骨髓纤维化的关键性血细胞系和炎性因子；以Jak2 V617F基因敲入小鼠为研究对象,确定HIF-1α在有JAK2V617F突变的骨髓纤维化中的重要作用，同时探讨其他生长因子（TGF-β1）在骨髓纤维化中的协同作用机制。本课题旨在深入探讨MPN和MDS患者发生骨髓纤维化的共同分子机制，建立一个骨髓纤维化预防策略和治疗靶标，具有十分重要意义。

MPN 和 MDS 都是起源于有缺陷的造血干细胞/祖细胞的慢性克隆性疾病。在 MPN 或 MDS 患者中常伴有骨髓纤维化，预后不良。我们前期在 MLL-PTD/mRUNX1- MDS 小鼠模型研 究中发现，HIF-1α 及其下游靶基因激活，与 MDS 合并骨髓纤维化密切相关;在 Jak2 V617F 鼠 模型中， Jak2 V617F 是否与 HIF-1α 共同作用导致骨髓纤维化机制尚不明确。整个课题预期内完成骨髓纤维化及真性红细胞增多症小鼠模型的建立，并明确HIF-1α 作为骨髓纤维化的关键内源性因子。由于JAK2突变而过度激活红细胞中EPO/JAK2/HIF信号，促进红系与巨噬细胞trogocytosis的发生，并令巨噬细胞获得红系前体细胞表面的EPOR，从而在EPO信号刺激下扩增和活化，成为诱发骨髓纤维化和真性红细胞增多发生的外源性因素。本课题创新点在于首次发现或揭示了:（1）HIF1A信号通路的激活是MDS和MPN的共同发病机制中起重要作用，HIF1A信号通路的激活，能有效提高MDS小鼠生存率。（2）红细胞和巨噬细胞之间通过trogocytosis，交换细胞膜EPOR，从而激活巨噬细胞JAK2信号，对红细胞和巨噬细胞的增殖和纤维化发生的外源性调控作用。