Role of TRAF6 in Myelodysplastic Syndromes

描述（由申请人提供）：骨髓增生异常综合征（MDS）是起源于缺陷造血干细胞（HSC）的血液恶性肿瘤，定义为无效造血导致的血细胞减少、急性髓性白血病（AML）易感性和基因组不稳定性。我们最近鉴定了miR-146 a，这是MDS中染色体5 q缺失片段（del（5 q））的一部分。在del（5 q）或正常核型MDS中，miR-146 a的表达减少导致TRAF 6的蛋白质表达增加，TRAF 6是miR-146 a的关键靶点和先天免疫信号传导的介体。因此，我们假设慢性先天免疫信号传导（由TRAF 6介导）部分通过重新编程HSC的代谢状态而促成MDS和AML的进展。我们还提出，先天免疫途径抑制将抑制MDS和AML增殖细胞。基于这些观察结果，我们将（1）确定从MDS向AML进展期间HSC中通过TRAF 6的慢性先天免疫信号传导的作用，（2）确定MDS/AML对TRAF 6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这种疾病的障碍。MDS中TRAF 6机制的鉴定将影响MDS/AML的诊断、分子分期和靶向治疗，并阐明TRAF 6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.