Molecular Mechanisms of Myelokathexis

描述（由申请人提供）：骨髓增生异常综合征是一种罕见的先天性常染色体显性遗传疾病，其特征是严重的慢性中性粒细胞减少或白细胞减少。患者的白细胞水平极低，特别是外周循环中的成熟中性粒细胞，范围为0至0.5x109 /L。骨髓细胞病变的特征是骨髓中存在成熟的中性粒细胞，其核叶与细丝相连。患者经历复发性感染，包括中耳炎和外耳炎、HPV、牙龈炎以及严重的皮肤和鼻窦感染。在一些但不是所有的患者中，疣、低丙种球蛋白血症和复发性支气管肺炎感染与骨髓增生异常综合征（W.H.I.M.综合征）。骨髓增生异常综合征患者可能发展为致死性B细胞淋巴瘤，然而，这些患者中未报告与感染相关的早期死亡，这可能是由于感染发作期间成熟骨髓中性粒细胞动员所致。CXCR 4基因的突变已在大多数骨髓增生异常患者中被发现。我们克隆了突变基因产物并在人骨髓祖细胞中表达。我们建议建立一个基于tet调控的突变型CXCR 4表达的髓样病变模型，以进一步剖析介导髓样病变发展的分子事件。我们还将在NOD-SCID小鼠体内测试该模型，并将确定所鉴定的抑制剂在体内的功效。这些研究将为在骨髓增生异常综合征患者中开展临床试验奠定必要的基础。公共卫生相关性：我们和其他人报道了细胞过早死亡，并确定了患有复发性感染的骨髓炎患者的基因突变[1，2]。这些患者可能发展为致命性B细胞淋巴瘤[3]。我们建议建立这种疾病的细胞模型，并在小鼠体内进行测试。我们将使用这个模型来检查所鉴定的化合物的功效，这些化合物似乎可以阻断由这种突变基因引起的异常并恢复正常表型。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，然后在患者中开始临床试验。

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.