Molecular Pathogenesis of MDS

描述（由申请人提供）：骨髓增生异常综合征（MDS）起源于有缺陷的造血干细胞（HSC），由造血无效、骨髓发育不良和基因组不稳定引起的血细胞减少定义。免疫相关基因的过度表达在MDS中被广泛报道，慢性先天免疫通路激活增加了MDS发生的风险。我们发现TNF受体相关因子6 （TRAF6）是一种位于先天免疫通路中心的泛素连接酶，在低风险MDS患者中过表达，这可能解释了MDS启动HSC中免疫通路激活的原因。根据我们的初步数据，TRAF6在小鼠中的过表达通过直接泛素化剪接因子导致MDS和全局mRNA剪接改变。因此，我们假设TRAF6的异常表达通过直接调节剪接体导致HSC缺陷，进而导致MDS。我们的长期目标是通过研究与MDS发病机制相关的分子改变来了解MDS。这个目标的核心是我们对先天免疫途径对MDS的贡献的兴趣。本研究的目的是：(1)建立TRAF6过表达对HSC功能、MDS启动和维持的细胞机制；(2)确定TRAF6在MDS中改变基因剪接的机制。对于TRAF6过表达（MDS中上调的基因）如何导致类似MDS的造血缺陷，将获得有价值的见解。

DESCRIPTION (provided by applicant): 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.