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

del(5q) 骨髓增生异常综合征基因的鉴定和表征

基本信息

批准号：
8770052
负责人：
Daniel Starczynowski
金额：
$ 37.68万
依托单位：
CINCINNATI CHILDRENS HOSP MED CTR
依托单位国家：
美国
项目类别：
财政年份：
2011
资助国家：
美国
起止时间：
2011-12-15 至 2015-11-30
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/8770052
关键词：
5q31.1 Acute Myelocytic Leukemia Adaptor Signaling Protein Address Binding Blood Blood Cells Bone Marrow CD34 gene Cell Survival Cell physiology Cell-Free System Cells Chromosome Deletion Chromosomes Clinical Collection DNA Sequence Alteration Data Defect Development Disease Disease Progression Distal Dysmyelopoietic Syndromes Dysplasia Exhibits FHA Domain Failure Fibroblasts Frequencies Functional disorder Genes Genetic Genomic Instability Goals Grant Hematologic Neoplasms Hematopoiesis Hematopoietic Human Ineffective Hematopoiesis Literature Maps Marrow Measures Mediating MicroRNAs Molecular Mus Myeloid Cells Myeloproliferative disease Pathway interactions Patients Phenotype Play Predisposition Production Proteins Publishing RNA Interference Reporting Research Role Sampling Signal Pathway Signal Transduction Stem cells TRAF-Interacting Protein TRAF6 gene Testing Tumor Necrosis Factor Receptor base cell growth chromosome 5q loss cytopenia design in vivo inhibitor/antagonist insight interest leukemia mouse model novel novel therapeutics overexpression protein expression response stem

项目摘要

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.

描述（由申请人提供）：骨髓增生性综合征（MDS）是由于造血症，基因组不稳定性，基因组不稳定性和白血病的倾向，由血细胞质症定义的克隆骨髓衰竭障碍。 MDS中最反复发生的基因组改变是5Q染色体（DEL（5Q））的缺失。在CHR 5Q上映射了两个常见的删除区域（CDR）（频段Q31.1和Q33.1）；然而，尚未鉴定出有助于造血干细胞/祖细胞（HSPC）的CDR中的基因。我们最近确定了远端CDR的miR-146a在DEL（5Q）MDS患者中显着降低。 HSPC中MiR-146a或其靶标TRAF6的过表达导致小鼠MDS样疾病。搜索CDR内或附近的注释基因揭示了另一种已知的TRAF6抑制剂，Traf6，Traf相互作用蛋白与与叉子相关的结构域B（TIFAB），在5q31.1上（在近端CDR中）。 TIFAB结合并抑制TIFA，TIFA是TRAF6激活必不可少的蛋白质。我们假设TIFAB缺失会导致HSPC缺陷通过促进TRAF6的过度激活而导致DEL（5Q）MDS，并提出同时损失TIFAB和MIR-146A协同激活HSPC中HSPC的TRAF6诱导更准确的疾病。初步数据表明，RNAi介导的TIFAB的敲低或遗传缺失导致小鼠MDS样缺陷。该提案的目标是（1）调查TIFAB在HSPC功能上的损失以及对MDS的贡献；（2）确定TIFAB缺失对TRAF6激活的后果，以及这些是否可以解释MD的特征；（3）研究TIFAB和miR-146A的缺失是否通过TRAF6激活启动MDS。鉴于MDS的分子基础的定义很差，我们希望TIFAB的特征将有助于理解MDS中新型治疗剂的分子缺陷和设计。