Aberrant Ubiquitin-Editing in the Pathogenesis of Myeloid Malignancies

 描述(申请人提供)：骨髓增生异常综合征(MDS)是一种克隆性造血干细胞(HSC)疾病，在这种疾病中，造血功能失调会导致外周血细胞减少，并与发展为急性髓系白血病(AML)的倾向增加有关。目前的MDS模型解释说，癌前造血干细胞获得克隆优势，并胜过健康的造血干细胞，导致无效的造血。我们已经证实，在MDS患者分离的HSC中，参与免疫信号负反馈调节的双重泛素编辑蛋白TNFAIP3(A20)的表达下调。此外，我们的初步数据显示，小鼠HSCs中A20的缺失会导致体内造血功能受损，继而导致致命的血液系统恶性肿瘤。这一发现表明，A20对HSC的功能是必不可少的；然而，A20保护正常造血和防止MDS的机制仍不清楚。本研究项目的目的是了解A20的泛素编辑功能异常如何在造血应激和MDS的启动中起作用。我们假设A20介导的泛素编辑的丢失通过干扰泛素信号来驱动MDS并损害HSC的存活。为了阐明这一机制并验证我们的假设，我们开发了两个目标：目标1将确定A20丢失对HSC功能的影响并进展为MDS和AML；目标2将确定A20的去泛素化结构域或E3连接酶结构域对HSC功能的要求。我们的研究将揭示20‘S在MDS的发生和发展中的意义。了解A20缺失在MDS进展中的机制将使未来的研究能够确定MDS患者的治疗靶点。

 DESCRIPTION (provided by applicant): Myelodysplastic Syndromes (MDS) are clonal hematopoietic stem cell (HSC) disorders in which dysregulated hematopoiesis leads to cytopenias of the peripheral blood and are associated with an increased propensity to develop Acute Myeloid Leukemia (AML). The current model of MDS explains that pre-malignant HSCs acquire a clonal advantage and outcompete healthy HSCs leading to ineffective hematopoiesis. We have established that expression of TNFAIP3 (A20), a dual ubiquitin-editing protein involved in the negative feedback regulation of immune signaling, is downregulated in HSCs isolated from MDS patients. Furthermore, our preliminary data shows that deletion of A20 in mouse HSCs results in impairment of hematopoiesis in vivo followed by a fatal hematologic malignancy. This findings suggest that A20 is essential for HSC function; however, the mechanism by which A20 preserves normal hematopoiesis and prevents MDS remains unknown. The goal of this research project is to understand how aberrant ubiquitin-editing function of A20 contributes to hematopoietic stress and initiation of MDS. We hypothesize that loss of A20-mediated ubiquitin-editing drives MDS and impairs HSC survival by perturbed ubiquitin signaling. To elucidate this proposed mechanism and test our hypothesis, two aims have been developed: Aim 1 will establish the consequences of A20 loss on HSC function and progression to MDS and AML; and, Aim 2 will determine the requirement of either the deubiquitination domain or the E3 ligase domain of A20 on HSC function. Our studies will reveal A20's implication in the initiation and progression of MDS. Understanding the mechanism of A20 loss on MDS progression will enable future studies to identify therapeutic targets for MDS patients.