Molecular Pathogenesis of MDS

摘要 骨髓增生异常综合征（MDS）起源于造血干细胞缺陷 细胞（HSC），并定义为由于无效的 造血、骨髓发育不良和基因组不稳定。过表达 免疫相关基因在MDS和慢性先天性免疫性骨髓增生异常综合征中被广泛报道， 通路激活增加了发生MDS的风险。我们发现TNF 受体相关因子6（TRAF 6），是一种泛素连接酶，位于血管内皮细胞的中枢， 先天免疫途径，在低风险MDS患者中过表达， 解释MDS启动HSC中的免疫途径激活。根据我们 初步数据显示，TRAF 6在小鼠中的过表达导致MDS， 通过直接泛素化剪接因子改变mRNA剪接。因此，我们认为， 我们假设TRAF 6的异常表达导致HSC缺陷， 通过直接调节剪接体导致MDS。我们的长期目标是 通过研究与MDS相关的分子改变来了解MDS 发病机制这一目标的核心是我们对先天性的贡献感兴趣， MDS的免疫途径。本提案的目标是：（1）建立 TRAF 6过表达对HSC功能和MDS的细胞机制 启动和维持;（2）确定改变基因的机制 在MDS中通过TRAF 6剪接。将获得关于TRAF 6如何 在MDS中上调的基因过表达可能有助于造血功能的恢复。 类似MDS的缺陷。

Abstract Myelodysplastic syndromes (MDS) originate from a defective hematopoietic stem cell (HSC), and are defined by blood cytopenias due to ineffective hematopoiesis, myeloid dysplasia, and genomic instability. Overexpression of immune-related genes is widely reported in MDS and chronic innate immune pathway activation increases the risk for developing MDS. We find that TNF receptor associated factor 6 (TRAF6), a ubiquitin ligase within the hub of the innate immune pathway, is overexpressed in low-risk MDS patients, and may explain immune pathway activation in the MDS-initiating HSC. According to our preliminary data, TRAF6 overexpression in mice results in MDS and global mRNA splicing alterations by directly ubiquitinating a splicing factor. Therefore, we hypothesize that aberrant expression of TRAF6 results in HSC defects contributing to MDS by directly regulating the spliceosome. Our long-term goal is to understand MDS by investigating molecular alterations associated with MDS pathogenesis. Central to this goal is our interest in the contribution of innate immune pathway to MDS. The objectives of this proposal are to (1) establish the cellular mechanism of TRAF6 overexpression on HSC function, and MDS initiation and maintenance; and (2) determine the mechanism of altered gene splicing by TRAF6 in MDS. Valuable insight will be gained on how TRAF6 overexpression, a gene upregulated in MDS, may contribute to hematopoietic defects resembling MDS.