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）是由造血功能低下、基因组不稳定和易患白血病导致的血细胞减少所定义的克隆性骨髓衰竭疾病。MDS中最常见的基因组改变是5q染色体缺失（del(5q)）。在chr 5q上发现了两个常见的缺失区（q31.1和q33.1波段）；然而，cdr中导致骨髓细胞发育异常或造血干细胞/祖细胞（HSPC）生存优势的基因尚未被确定。我们最近发现，位于远端CDR附近的miR-146a在del(5q) MDS患者中显著降低。在HSPC中缺失miR-146a或其靶点TRAF6过表达会导致小鼠出现mds样疾病。对CDR内或附近的注释基因的搜索发现了另一种已知的TRAF6抑制剂，traf1与叉头相关结构域B （TIFAB）相互作用蛋白，位于5q31.1（近端CDR内）。TIFAB结合并抑制TIFA，这是TRAF6激活所必需的蛋白质。我们假设TIFAB缺失通过促进TRAF6的过度激活导致HSPC缺陷，从而导致del(5q) MDS，并提出TIFAB和miR-146a同时缺失可协同激活HSPC中的TRAF6，从而更准确地诱导疾病。初步数据显示，rnai介导的TIFAB基因敲低或基因缺失会导致小鼠出现mds样缺陷。本研究的目的是：(1)研究TIFAB在HSPC功能上的缺失及其对MDS的贡献；(2)确定TIFAB缺失对TRAF6激活的影响，以及这些是否可以解释MDS的特征；(3)研究TIFAB和miR-146a的缺失是否通过TRAF6激活协同启动MDS。鉴于MDS的分子基础尚不明确，我们希望TIFAB的表征将有助于理解MDS的分子缺陷和设计新的治疗方法。

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.