Analysis of pathogenesis and pathophysiology of congenital bone marrow failure for the establishment of the treatment strategy

先天性骨髓衰竭发病机制和病理生理学分析以制定治疗策略

• 批准号: 15591114
• 负责人: OHGA Shouichi
• 金额: $ 1.92万
• 依托单位: Kyushu University
• 依托单位国家: 日本
• 项目类别: Grant-in-Aid for Scientific Research (C)
• 财政年份: 2003
• 资助国家: 日本
• 起止时间: 2003 至 2004
• 项目状态: 已结题
• 来源: https://kaken.nii.ac.jp/en/grant/KAKENHI-PROJECT-15591114/
• 关键词: congenital bone marrow failure syndrome; Diamond-Blackfan anemia; immunosuppressive therapy; hematopoietic stem cell transplantation; microarray; ribosome protein; RPS19; inherited bone marrow failure syndrome

Diamond-Black fan anemia(DBA) is a congenital pure red cell aplasia occasionally presenting physical anomalies. Approximately 20% of patients carry the heterozygous mutation of ribosomal protein S19 gene(RPS19). However, the etiopathogenesis of erythroblastopenia and anomalies due to the haploinsufficiency remains elusive, and other causative genes are suggested. A part of patients depend on transfusion and/or prednisolone(PSL), and then require hematopoietic stem cell transplantation(HSCT). In Japan, there has been neither information on the epidemiology of DBA, nor reported patients having the mutation of RPS19. Clinical and experimental analyses of congenital (inherited) bone marrow failure syndrome will provide useful informaion not only for the management of patients, but also for clarifying the molecular mechanism of hematopoiesis and morphogenesis. We studied the epidemiology and treatment responses of DBA patients in Japan, and revealed the outcomes and problems of HSCT, based … More on the follow-up data in the registration of the Aplastic Anemia Committee of the Japanese Society of Pediatric Hematology (Professors, Tsukimoto I, Mugishima H, Ohara A, Kojima S, et al.). Furthermore, we analyzed the gene expressions of representative patients carrying no RPS19 mutations, and suggested that reduced expression ofnon-mutated RP genes might be involved in the underlying mechanism of constitutional anemia1)Epidemiology and treatment responsesA cohort of 54 children (M:F=26:28) registered in Japan from 1988 to 1998 was surveyed. The annual incidence was 4.02 cases per million births, median age at diagnosis was 60 days, and 59% presented by 3 months of age. Three patients had a familial occurrence. All received PSL, and cyclosporine-A(CsA) was combined in 17 patients. Forty-seven received transfusions, and 13 underwent HSCT. The cumulative probability of a medication-or transfusion-free state prior to HSCT was 36% or 69%, respectively, more than 5 years after diagnosis. Thirteen patients were weaned from PSL-therapy without HSCT, and CsA was not associated with weaning from the therapy. Transfusion and medication were stopped at 249 and 933 days after diagnosis in 34 and 13 patients, respectively, who achieved a state ofindependency. HSCT led to the highest success (85%) of all previous reports, even though 5 alternative donors were included in our study.2)Microarray analysis by using Oligo DNA tip covering nearly all human genomesGene expression patterns of CD4^+ cells were compared in representative patients between DBA and AA. Differences in the gene expression levels between DBA and aplastic anemia(AA) did not reach the statistical significance. K-mean clustering analysis revealed the significant categorization of 28 RP genes into a small set of group (994 genes)(p=2.39E-17)5 in which all genes were expressed at lower levels in DBA than in AA patients. RPS19 was categorized into the set of low expressing genes in DBA patients. These results indicated that the lower expression of RP genes was a distinctive feature of DBA from AA. Less

钻石黑扇形贫血（DBA）是一种先天性纯红细胞再生障碍性贫血，偶尔出现身体异常。约20%的患者携带核糖体蛋白S19基因（RPS 19）杂合突变。然而，由于单倍不足引起的成红细胞减少症和异常的发病机制仍然难以捉摸，并提出了其他致病基因。部分患者依赖输血和/或泼尼松龙（PSL），然后需要造血干细胞移植（HSCT）。在日本，既没有关于DBA流行病学的信息，也没有报告具有RPS 19突变的患者。对先天性（遗传性）骨髓衰竭综合征的临床和实验研究，不仅可以为临床治疗提供有用的信息，而且有助于阐明造血和形态发生的分子机制。我们研究了日本DBA患者的流行病学和治疗反应，并揭示了HSCT的结果和问题， ...更多信息 关于日本儿科血液学会再生障碍性贫血委员会注册的随访数据（教授，Tsukimoto I，Mugishima H，大原A，Kojima S，等）。此外，我们分析了代表性的无RPS 19突变的患者的基因表达，并提出非突变的RP基因的表达减少可能参与体质性贫血的潜在机制1）流行病学和治疗反应调查了1988年至1998年在日本登记的54名儿童（男：女=26：28）的队列。年发病率为4.02例/百万新生儿，诊断时的中位年龄为60天，59%在3个月大时出现。3例患者发生家族性事件。所有患者均接受PSL治疗，17例患者联合环孢霉素A（CsA）。47例接受了输血，13例接受了HSCT。在诊断后5年以上，HSCT前无药物或无输血状态的累积概率分别为36%或69%。13例患者在未进行HSCT的情况下脱离了PSL治疗，CsA与脱离治疗无关。分别有34名和13名患者在诊断后249天和933天停止输血和药物治疗，并达到不依赖状态。HSCT的成功率为85%，是以往报道中最高的，尽管我们的研究中包括了5个替代供体。2）使用Oligo DNA探针进行的微阵列分析几乎覆盖了所有人类基因组。DBA与再生障碍性贫血（AA）的基因表达水平差异无统计学意义。K-均值聚类分析显示28个RP基因被显著分类为一小组（994个基因）（p=2.39E-17）5，其中所有基因在DBA中的表达水平低于AA患者。RPS 19在DBA患者中被归类为低表达基因组。这些结果表明，RP基因的低表达是DBA与AA的显著区别。少

项目成果

Successful umbilical cord blood transplantation for severe CAEBV after double failures of hematopoietic stem cell transplanation

造血干细胞移植两次失败后成功脐带血移植治疗重症CAEBV

• 发表时间: 2005
• 期刊: Am J Haematol (in press)
• 作者: Ishimura M;Ohga S;Nomura A;et al.
• 通讯作者: et al.

Increased serum levels of interferon-γ-inducible protein 10 and monokine induced by gamma interferon in patients with hemophagocytic lymphohistiocytosis.

噬血细胞性淋巴组织细胞增多症患者中γ干扰素诱导的干扰素-γ-诱导蛋白10和单核因子的血清水平升高。

• 发表时间: 2003
• 期刊: Clin Exp Immunol 133
• 作者: Takada H;Takahata Y;Nomura A;Ohga S;Mizuno Y;Hara T
• 通讯作者: Hara T

Ohga S, Mugishima H, et al.: "Diamond-Blackfan anemia in Japan : Outcomes of prednisolone therapy and hematopoietic stem cell transplantation"Int J Hematol. 79. 22-30 (2004)

Ohga S、Mugishima H 等：“日本的 Diamond-Blackfan 贫血：泼尼松龙治疗和造血干细胞移植的结果”Int J Hematol。

菅尚浩, 高田英俊, 大賀正一, 金兼弘和, 宮脇利男, 原寿郎: "リンパ球の活性化抑制とパーフォリン-家族性血球貧食リンパ組織球症の成因-"臨床免疫. 40. 110-116 (2003)

Naohiro Suga、Hidetoshi Takada、Shoichi Ohga、Hirokazu Kanekane、Toshio Miyawaki、Juro Hara：“抑制淋巴细胞活化和穿孔素 - 家族性血友病性淋巴组织细胞增多症的原因 -”临床免疫学。 40. 110-116 (2003)

Proposed guidelines for diagnosing chronic active Epstein-Barr virus infection

• DOI: 10.1002/ajh.20398
• 发表时间: 2005-09-01
• 期刊: AMERICAN JOURNAL OF HEMATOLOGY
• 影响因子: 12.8
• 作者: Okano, M;Kawa, K;Imashuku, S
• 通讯作者: Imashuku, S