Molecular Mechanisms of Myelokathexis

描述(申请人提供)：骨髓畸形是一种罕见的先天性常染色体显性遗传病，以严重的慢性中性粒细胞减少或白细胞减少为特征。患者外周血中白细胞水平极低，尤其是外周血中成熟的中性粒细胞在0~0.5x109/L之间。骨髓异常的特征是骨髓中存在成熟的中性粒细胞，核叶与细丝相连。患者经历了反复感染，包括中耳炎和外耳炎，HPV，牙周炎，以及严重的皮肤和鼻窦肺部感染。在一些(但不是全部)患者中，疣、低丙种球蛋白血症和复发性支气管肺感染与骨髓异常(W.H.I.M.综合征)有关。骨髓异常综合征患者可能发展为致命性B细胞淋巴瘤，然而，没有报道这些患者与感染有关的早期死亡，这可能是由于在感染期间动员了成熟的骨髓中性粒细胞。CXCR4基因的突变已在大多数骨髓畸形患者中被发现。我们克隆了突变的基因产物，并在人髓系祖细胞中表达。我们建议建立一种基于突变型CXCR4的tet调控表达的脊髓损伤模型，以进一步剖析介导骨髓损伤发生的分子事件。我们还将在NOD-SCID小鼠体内测试这一模型，并将在体内确定已确定的抑制剂的疗效。这些研究将为启动骨髓紧张症患者的临床试验奠定重要的基础。公共卫生相关性：我们和其他人报告了反复感染的骨髓畸形患者的细胞过早死亡和基因突变[1，2]。这些患者可能发展成致命的B细胞淋巴瘤[3]。我们建议建立这种疾病的细胞模型，并在小鼠身上进行体内测试。我们将使用这个模型来检验已鉴定的化合物的有效性，这些化合物似乎可以阻止该突变基因造成的异常，并恢复正常的表型。在开始对患者进行临床试验之前，我们将研究这种药物及其类似物在这种疾病的细胞和动物模型中的疗效。

DESCRIPTION (provided by applicant): Myelokathexis is a rare congenital autosomal dominant disorder characterized by severe chronic neutropenia or leukopenia. The patients have extremely low levels of leukocytes, particularly mature neutrophils in peripheral circulation ranging from 0 to 0.5x109 /L. The characteristic feature of myelokathexis is a presence of bone marrow mature neutrophils with nuclear lobs connected with thin filaments. The patients experience recurrent infections including otitis media and otitis externa, HPV, gingivitis, and severe cutaneous and sinopulmonary infections. In some but not all patients, there is an association of Warts, Hypogammaglobulinemia, and recurrent bronchopulmonary Infections with Myelokathexis (W.H.I.M. syndrome). Myelokathexis patients may evolve to develop fatal B-cell lymphoma, however, no early death related to infections in these patients was reported which is probably due to mobilization of mature marrow neutrophils during infection episodes. Mutations in the CXCR4 gene have been identified in most of the patients with myelokathexis. We cloned the mutant gene products and expressed them in human myeloid progenitor cells. We propose to establish a model of myelokathexis based on tet-regulated expression of mutant CXCR4 in order to further dissect the molecular events mediating development of myelokathexis. We will also test this model in vivo in NOD-SCID mice and will determine the efficacy of identified inhibitors in vivo. These studies will pave important foundation necessary for initiating of clinical trials in patients with myelokathexis. PUBLIC HEALTH RELEVANCE: We and others reported premature cell death and identified gene mutations in patients with myelokathexis who suffer from recurring infections [1,2]. These patients may evolve to develop fatal B-cell lymphoma [3]. We propose to establish a cellular model of this disease and test it in vivo in mice. We will use this model to examine the efficacy of identified compounds, which appear to block the abnormalities caused by this mutant gene and restore the normal phenotype. We will study the efficacy of this drug and its analogs in the cellular and animal models of this disease prior to initiating clinical trials in patients.