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

钻石黑色的风扇贫血（DBA）是一种纯净的红色，表现出物理状态。 Oietic干细胞移植（HSCT）。患者的管理研究了日本DBA患者的流行病学和治疗反应，并揭示了HSCT的结果和问题...更多关于日本儿科血液学学会的促促性贫血委员会的随访数据的更多信息，Ohara A，Kojima S等）。 M：F = 26：28）在1988年至1998年间在日本注册。年度发病率为4.02 llion出生，诊断时中位年龄为60天，在3个月中出现了59％。融合和13个融合，在诊断后的13例患者中，HSCT的累积概率为36％或69％在34例和13例患者中，在诊断后的249天和933天停止了药物，即使在我们的研究中包括了5个替代供体，但有5个替代供体。在DBA和AA之间的抑制性患者中，CD4^+细胞的基因组表达在DBA和性贫血之间的表达水平（AA）中没有达到统计学意义。一组基因（P = 2.39E-17）5，其中所有基因在DBA中都比AA患者分类为RPS19。基因是AA的DBA的独特特征。

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。