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

钻石黑色扇形贫血（DBA）是一种先天性纯红细胞，有时会呈现身体异常。大约20％的患者携带核糖体蛋白S19基因的杂合突变（RPS19）。然而，由于单倍不足，红细胞多症和异常异常的病毒作用仍然难以捉摸，并提出了其他严重的基因。一部分患者取决于输血和/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，也没有报告患者的突变RPS19。先天性（遗传）骨髓衰竭综合征的临床和实验分析不仅可以为患者的管理提供有用的信息，还可以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……更多的基于日本儿科血液学副贫血委员会的后续数据，更多的后续数据（Tsukimoto I，Mugishima H，Ohara h，Ohara a，Kojima a，Kojima s等）。此外，我们分析了携带NO RPS19突变的代表性患者的基因表达，并建议降低非突变的RP基因的表达可能与宪法性贫血的基本机制有关。每年的发病率为每百万分出生4.02例，诊断时中位年龄为60天，59％在3个月大时出现。三名患者发生家庭。所有接受的PSL，环孢素A（CSA）合并为17名患者。四十七个接受了输血，13例接受了HSCT。诊断后5年以上，在HSCT之前，无药或无输血状态的累积概率分别为36％或69％。在没有HSCT的情况下，将13名患者从PSL疗法中断奶，而CSA与治疗中的断奶无关。诊断后的249和933天，分别在34例和13名患者中，输血和药物在249天和933天停止了，他们实现了独立状态。 HSCT导致了所有先前报告的最高成功（85％），即使我们的研究中包括了5个替代捐助者。2）在DBA和AA之间的代表性患者中比较了使用寡核DNA尖端覆盖CD4^+细胞几乎所有人类基因组表达模式的微阵列分析。 DBA和性贫血（AA）之间基因表达水平的差异未达到统计学意义。 K-均值聚类分析揭示了28个RP基因的显着类别分为一组小组（994个基因）（p = 2.39e-17）5，其中所有基因在DBA中的表达在DBA的水平低于AA患者。 RPS19分为DBA患者的低表达基因。这些结果表明，RP基因的较低表达是DBA与AA的独特特征。较少的

项目成果

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

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.

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)

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。