Role of TRAF6 in Myelodysplastic Syndromes

描述(申请人提供)：骨髓增生异常综合征(MDS)是起源于缺陷的造血干细胞(HSC)的血液系统恶性肿瘤，由无效的造血、易患急性髓系白血病(AML)和基因组不稳定引起的血细胞减少来定义。我们最近发现了miR-146a，它是MDS染色体5q缺失片段(del(5q))的一部分。MiR-146a在del(5q)或正常核型MDS中表达减少，导致TRAF6蛋白表达增加，TRAF6是miR-146a的关键靶点，也是天然免疫信号的中介。因此，我们假设慢性先天免疫信号(由TRAF6介导)在MDS和AML进展中起一定作用，部分是通过重新编程HSC的代谢状态。我们还提出，先天免疫途径的抑制将抑制MDS和AML的增殖细胞。在这些观察的基础上，我们将(1)确定TRAF6在HSC从MDS向AML发展过程中的作用，(2)确定MDS/AML对TRAF6的致癌依赖性，(3)研究MDS HSC中HSC的代谢再编程。MDS的复杂性和缺乏小鼠模型是有效治疗这种疾病的障碍。MDS中TRAF6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MDS中通过AKT和/或NF-κB的代谢重编程之间的新的临床相关联系。

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-κB in MDS.