No abstract

Both nuclear factor erythroid 2 45 kDa subunit (p45) and BTB and CNC homolog 1 (Bach) transcription factors can form dimers with one of the small Maf proteins, and these heterodimers bind to the musculoaponeu-rotic fibrosarcoma oncogene (Maf) recognition element (MARE). MARE is known to act as a critical cis-regulatory element of ery-throid and megakaryocytic genes. Although detailed analyses of p45-null mutant mice and small maf compound mutant mice revealed that these factors are both critical for platelet production, the functional contributions of Bach1 and the relationship or redundancy between Bach1 and p45 in megakaryocytes remain to be clarified. To address these issues, we generated trans-genic lines of mice bearing human BACH1 cDNA under the control of the GATA-1 locus hematopoietic regulatory domain. The trans-genic mouse lines showed significant throm-bocytopenia associated with impaired matu-ration of the megakaryocytes, and they developed myelofibrosis. The megakaryo-cytes in the transgenic mice exhibited reduced proplatelet formation, and the modal ploidy class of megakaryocytes was 2N, indicating the impairment of endomitosis. Transcription of the p45 target genes was down-regulated and we indeed found that BACH1 binds to the thromboxane synthase gene, one of the target genes for p45 in megakaryocytes. These findings thus provide evidence that BACH1 acts as a tran-scriptional repressor in the regulation of MARE-dependent genes in megakaryocytes. (Blood. 2005;105:3100-3108)

Inherited bone-marrow-failure syndromes (IBMFSs) include heterogeneous genetic disorders characterized by bone-marrow failure, congenital anomalies, and an increased risk of malignancy. Many lines of evidence have suggested that p53 activation might be central to the pathogenesis of IBMFSs, including Diamond-Blackfan anemia (DBA) and dyskeratosis congenita (DC). However, the exact role of p53 activation in each clinical feature remains unknown. Here, we report unique de novo TP53 germline variants found in two individuals with an IBMFS accompanied by hypogammaglobulinemia, growth retardation, and microcephaly mimicking DBA and DC. TP53 is a tumor-suppressor gene most frequently mutated in human cancers, and occasional germline variants occur in Li-Fraumeni cancer-predisposition syndrome. Most of these mutations affect the core DNA-binding domain, leading to compromised transcriptional activities. In contrast, the variants found in the two individuals studied here caused the same truncation of the protein, resulting in the loss of 32 residues from the C-terminal domain (CTD). Unexpectedly, the p53 mutant had augmented transcriptional activities, an observation not previously described in humans. When we expressed this mutant in zebrafish and human-induced pluripotent stem cells, we observed impaired erythrocyte production. These findings together with close similarities to published knock-in mouse models of TP53 lacking the CTD demonstrate that the CTD-truncation mutations of TP53 cause IBMFS, providing important insights into the previously postulated connection between p53 and IBMFSs.

BackgroundAlthough the therapeutic outcome of acquired aplastic anemia has improved markedly with the introduction of immunosuppressive therapy using antithymocyte globulin and cyclosporine, a significant proportion of patients subsequently relapse and require second-line therapy. However, detailed analyses of relapses in aplastic anemia children are limited. Design and MethodsWe previously conducted two prospective multicenter trials of immunosuppressive therapy for children with aplastic anemia: AA-92 and AA-97, which began in 1992 and 1997, respectively. In this study, we assessed the relapse rate, risk factors for relapse, and the response to secondline treatment in children with aplastic anemia treated with antithymocyte globulin and cyclosporine. ResultsFrom 1992 to 2007, we treated 441 children with aplastic anemia with standard immunosuppressive therapy. Among the 264 patients who responded to immunosuppressive therapy, 42 (15.9%) relapsed. The cumulative incidence of relapse was 11.9% at 10 years. Multivariate analysis revealed that relapse risk was significantly associated with an immunosuppressive therapy regimen using danazol (relative risk, 3.15; P=0.001) and non-severe aplastic anemia (relative risk, 2.51; P=0.02). Seventeen relapsed patients received additional immunosuppressive therapy with antithymocyte globulin and cyclosporine. Eight patients responded within 6 months. Seven of nine non-responders to second immunosuppressive therapy received hematopoietic stem cell transplantation and five are alive. Eleven patients underwent hematopoietic stem cell transplantation directly and seven are alive. ConclusionsIn the present study, the cumulative incidence of relapse at 10 years was relatively low compared to that in other studies mainly involving adult patients. A multicenter prospective study is warranted to establish optimal therapy for children with aplastic anemia. Relapse of aplastic anemia in children after immunosuppressive therapy: a report from the Japan Childhood Aplastic Anemia Study Group