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

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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