Identification and characterization of genes in del(5q) myelodysplastic syndrome

描述（由申请人提供）：骨髓增生异常综合征（MDS）是一种克隆性骨髓衰竭疾病，定义为由于无效造血、基因组不稳定和白血病易感性导致的血细胞减少。MDS中最常见的基因组改变是染色体5 q的缺失（del（5 q））。两个常见的缺失区（CDR）已被定位在chr 5 q（带q31.1和q33.1）;然而，CDR内的基因，有助于发育不良的骨髓细胞或造血干/祖细胞（HSPC）的生存优势尚未确定。我们最近发现miR-146 a在del（5 q）MDS患者中显著降低，其位于远端CDR附近。HSPC中miR-146 a的缺失或其靶标TRAF 6的过表达导致小鼠中的MDS样疾病。对CDR内或附近的注释基因的搜索揭示了另一种已知的TRAF 6抑制剂，具有叉头相关结构域B的TRAF相互作用蛋白（TIFA B），位于5q31.1（在近端CDR内）。TIFAB结合并抑制TIFA，一种TRAF 6活化所必需的蛋白质。我们假设TIFAB缺失导致HSPC缺陷，通过促进TRAF 6的超活化而促成del（5 q）MDS，并提出TIFAB和miR-146 a的同时缺失协同激活HSPC中的TRAF 6以诱导更准确的疾病。初步数据显示，RNAi介导的TIFAB敲低或基因缺失导致小鼠中MDS样缺陷。本提案的目的是（1）研究TIFAB对HSPC功能的丧失和对MDS的贡献;（2）确定TIFAB缺失对TRAF 6激活的后果，以及这些是否可以解释MDS的特征;和（3）研究TIFAB和miR-146 a的缺失是否协同通过TRAF 6激活启动MDS。鉴于MDS的分子基础定义不明确，我们希望TIFAB的表征将有助于理解MDS的分子缺陷和新疗法的设计。

DESCRIPTION (provided by applicant): Myelodysplastic syndromes (MDS) are clonal marrow failure disorders defined by blood cytopenias due to ineffective hematopoiesis, genomic instability, and predisposition to leukemia. The most recurring genomic alteration in MDS is deletion of chromosome 5q (del(5q)). Two common deleted regions (CDRs) have been mapped on chr 5q (bands q31.1 and q33.1); however, the genes within the CDRs that contribute to dysplastic myeloid cells or to a survival advantage for hematopoietic stem/progenitor cells (HSPC) have not been identified. We recently identified miR-146a, which is near the distal CDR, to be significantly reduced in del(5q) MDS patients. Loss of miR-146a or overexpression of its target, TRAF6, in HSPC results in an MDS-like disease in mice. A search of annotated genes within or near the CDRs revealed another known inhibitor of TRAF6, TRAF-interacting protein with forkhead-associated domain B (TIFAB), on 5q31.1 (within the proximal CDR). TIFAB binds and inhibits TIFA, a protein essential for TRAF6 activation. We hypothesize that TIFAB deletion results in HSPC defects contributing to del(5q) MDS by promoting hyperactivation of TRAF6, and propose that simultaneous loss of TIFAB and miR-146a synergistically activate TRAF6 in HSPC to induce a more accurate disease. Preliminary data show that RNAi-mediated knockdown or genetic deletion of TIFAB results in MDS-like defects in mice. The objectives of this proposal are (1) to investigate the loss of TIFAB on HSPC function and the contribution to MDS; (2) to determine the consequences of TIFAB deletion on TRAF6 activation, and whether these could explain features of MDS; and (3) to investigate whether deletions of TIFAB and miR-146a cooperate to initiate MDS via TRAF6 activation. Given that the molecular basis of MDS is poorly defined, we hope that characterization of TIFAB will facilitate understanding the molecular defects and the design of novel therapeutics in MDS.