Role of TRAF6 in Myelodysplastic Syndromes

描述（由申请人提供）：骨髓增生异常综合征（MDS）是源自有缺陷的造血干细胞（HSC）的血液系统恶性肿瘤，由无效造血导致的血细胞减少、急性髓性白血病（AML）的易感性和基因组不稳定性定义。我们最近发现了miR-146a，这是MDS中染色体5q缺失片段的一部分（del(5q)）。无论是在del（5q）还是正常核型MDS中，miR-146a表达减少都会导致TRAF6蛋白表达增加，TRAF6是miR-146a的关键靶点，也是先天免疫信号传导的中介。因此，我们假设慢性先天免疫信号（由TRAF6介导）在一定程度上通过重编程HSC的代谢状态来促进MDS和AML的进展。我们还提出先天免疫途径抑制会抑制MDS和aml繁殖细胞。基于这些观察结果，我们将(1)确定慢性先天免疫信号通过TRAF6在MDS到AML进展中的作用，(2)确定MDS/AML对TRAF6的致癌依赖性，以及(3)研究MDS HSC中HSC代谢重编程。MDS的复杂性和小鼠模型的缺乏是有效治疗该病的障碍。TRAF6在MDS中的机制的确定将影响MDS/AML的诊断、分子分期和靶向治疗，并阐明TRAF6与AKT和/或NF-？B在MDS中。

DESCRIPTION (provided by applicant): Myelodysplastic syndromes (MDS) are hematologic malignancies originating from a defective hematopoietic stem cell (HSC), and defined by blood cytopenias due to ineffective hematopoiesis, a predisposition to acute myeloid leukemia (AML), and genomic instability. We recently identified miR-146a, a microRNA that is part of the deleted segment of chromosome 5q in MDS (del(5q)). Reduced expression of miR-146a, either in del(5q) or normal karyotype MDS, results in increased protein expression of TRAF6, a key target of miR-146a and a mediator of innate immune signaling. Therefore, we hypothesize that chronic innate immune signaling (mediated by TRAF6) contributes to MDS and progression to AML in part by reprogramming the metabolic state of HSC. We also propose that innate immune pathway inhibition will suppress MDS- and AML-propagating cells. Based on these observations, we will (1) define the role of chronic innate immune signaling via TRAF6 in HSC during the progression from MDS to AML, (2) determine the oncogenic dependency of MDS/AML on TRAF6, and (3) investigate HSC metabolic reprograming in MDS HSC. The complexity of MDS and paucity of mouse models are obstacles to effectively treating this disease. The identification of TRAF6 mechanisms in MDS will impact diagnosis, molecular staging, and targeted therapy for MDS/AML, and illuminate a novel and clinically-relevant connection between TRAF6 and metabolic reprogramming via AKT and/or NF-?B in MDS.