Cloning the genes at the breakpoint of chromosome translocations in leukemia leads to the clarification of the mechanism of leukemogenesis and normal hematopoiesis. Recently, the NUP98-HOXA9 fusion gene was identified in acute myeloid leukemia, myelodysplastic syndrome, and chronic myelogenous leukemia with t (7;11) (p15;p15), and a functional analysis was performed. Furthermore, 10 partner genes of the NUP98 were identified. Leukemias with these fusion genes were frequently discovered in therapy-related leukemia and found to have a poor prognosis. More recently, we found 3 partner genes of these fusion genes. Half of them have homeodomain in the 3' region, which is activated by a translocation of the NUP98 gene. Recent findings of partner genes of NUP98, especially HOX genes, are discussed in this review.

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Acute promyelocytic leukemia (APL) is a distinct subtype of leukemia characterized hematologically with maturation blockade at the stage of promyelocytes; cytogenetically with chromosome translocation involving 17q21, which generates retinoic acid receptor-α (RARα) chimeric gene; and clinically with differentiation-induction therapy with all-trans retinoic acid (ATRA). The genetic abnormality in APL exclusively disrupts theRARα gene by forming X-RARα, whereas the partner X-gene diversely involves PML in most patients and thePLZF, NPM, NuMA, or Stat5b gene in a few. Because X-RARα invariably has the DNA-binding and ligand-binding domains of RAR a, X-RARa inhibits in a dominant negative fashion the function of RARα as aRA-dependent transcription factor. In in vivo models, transgenic mice with PML-RARα or PLZF-RARαdevelop leukemia resembling APL, although an allelic inactivation of the X-gene may also play a role in the leukemogenesis of APL. It is interesting that the mechanism by which PML-RARα causes APL may also underlie differentiation-induction of APL with ATRA. In response to ATRA at pharmacological doses, PML-RARα releases corepressors and the histone deacetylase (HDAC) complex and recruits coactivators, which leads to a restoration of RA-responsive gene transcription. However, APL patients often acquire ATRA-resistance at relapse, which may be caused by acquired mutations in the RARα/E-domain of the PML-RARα gene. Therapy with arsenic acid or HDAC inhibitor may be of clinical use for refractory APL, and further investigation is needed.

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A retrospective comparative study was designed to assess the Quality of Life (QOL) in a group of children with acquired aplastic anemia (AA) treated with bone marrow transplantation (BMT) from HLA-matched sibling donors or immunosuppressive therapy (IST). We evaluated 19 children under the age of 14 years with AA who were treated in the Hospital of Hyogo College of Medicine from 1984 to 1999. Seven patients received IST and 13 patients BMT. The BMT group included one patient who was initially given 1ST. The good response rates for treatment were 85% for BMT and 86% for 1ST. No significant difference was noted between the two groups. Questionnaires for QOL assessment were completed by the patients' parents in November 1999. The results of a comparative study of QOL indicated that both groups equally showed an excellent level of satisfaction with their treatment. As for satisfaction in daily life, the IST group reported better status than the BMT group did. The physical late effects of BMT, such as chronic GVHD, affected QOL in the BMT group. Although many BMT patients reported marriage and employment as future anxiety, the IST patients were most anxious about relapse. The late effects of the treatment on QOL should be considered cautiously for the choice of an initial treatment of AA.

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We assessed the clinical features of the Adenovirus type 7 infection-associated hemophagocytic lymphohistiocytosis (AD7-HLH). Two boys and three girls aged 12 to 27 months developed AD7-HLH in the course of asthmatic bronchitis. Bone marrow aspirations were performed because of prolonged fever, hepatomegaly, cytopenia, and elevated levels of serum LDH and ferritin, and a diagnosis of HLH was determined. Two patients with complications from underlying diseases required mechanical ventilation as a result of respiratory failure. Characteristically, all patients developed consciousness disturbance, and two suffered convulsions. The examinations of their cerebrospinal fluid were normal, but their electroencephalogram showed a diffuse high-voltage slow wave. Brain CT showed a slight brain edema in two patients at diagnosis and a brain atrophy in two patients at recovery period. As a serious complication, a portal vein thrombosis occurred in one boy patient. Corticosteroids were administered and all patients recovered. Among the cytokines, the serum levels of sIL-2R, INF-γ, IL-6, and IL-18 were elevated and supposed to relate their consciousness disturbance.

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Dyskeratosis congenita (DC) is a rare inherited disease that is clinically characterized by the triad of abnormal skin pigmentation, nail dystrophy, and mucosal leucoplakia. Approximately 80% of the patients is associated with progressive bone marrow failure, and X-linked recessive inheritances are recognized in about 90%.In 1998, DKC1 was reported to be a causative gene for X-linked DC, and the DKC1 genetic analyses have been available. In the present study, we investigated DKC1 genes in the 4 patients with presumed X-linked DC and identified 3 missense mutations, such as Q31K, A353V, and T357A. A few DC patients may show aplastic anemia without skin manifestations. The genetic analysis is useful for the diagnosis of patients and carriers, as well as the differentiation of DC from acquired aplastic anemia.

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We evaluated the clinical features, treatment, and outcome of two patients with malignant lymphoma complicated by cardiac tamponade. The patients presented cough and dyspnea as the initial clinical signs. A mediastinal mass and pleural effusion were seen on chest X-ray films, suggesting cardiopulmonary disease initially. Pericardial effusions were detected by echocardiography in all cases_ and a volume raneine from 535 ml to over 1, 000 ml was removed by pericardiocentesis. A cytology of the pericardial effusion revealed T cell type lymphoblastic lymphoma (T-LBL). The first patient with T-NHL was treated by chemotherapy alone and 5 months later relapsed with another pericardial effusion. The second T-NHL patient was treated with chemotherapy plus radiotherapy to the tumor, but the effusion recurred at 8 months after presentation. These findings suggest that T-NHL complicated by pericardial effusion has a poor prognosis and should be treated with intense therapy including bone marrow transplant.

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We report on two infants with acute lymphoblastic leukemia (ALL) who suffered interstitial pneumonitis (IP) following hematopoietic stem cell transplantation. Case 1. An 8-month-old boy with ALL was treated in his second relapse with allogeneic cord blood stem cell transplantation (CBSCT) after conditioning with busulfan (BU), etoposide, and cyclophosphamide. Wheezing and tachypnea were observed from day 20 after CBSCT and diagnosed as IP by a chest-computed tomographic (CT) scan. Pulmonary infiltrates were resolved with methylprednisolone (m-PSL) pulse therapy. Case 2. An 8-month-old girl with ALL was treated in her first complete remission with a related bone marrow transplantation (BMT) after the same conditioning as case 1. Coughing and tachypnea were likewise observed from day 23 after BMT and diagnosed as IP by a chest CT scan. As in case 1, interstitial infiltrates disappeared after m-PSL pulse therapy. Neither case showed any evidence of virus infection. The BU blood level data in case 2 indicated that regimen-related toxicity (RRT) of BU might cause IP. No significant correlation between the risk of IP and BU level has been previously reported, but further data regarding pharmacokinetic monitoring of BU in infants may help confirm this correlation.

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Recently, immunosuppressive treatment has been reported to be effective for aplastic anemia. But hepatitis-associated aplastic anemia has poor prognosis and often requires hematopoietic stem cell transplantation. And few cases have been reported about immunosuppressive treatment for this condition. Here we present a 10-year-old boy suffering from hepatitis-associated aplastic anemia from unknown causes. We have treated him with immunosuppressive drugs including antithymocyte globulin, cyclosporin, and steroid because his liver dysfunction continued. As a result, his liver function and pancytopenia improved without severe side effects. These results suggest that immunosuppressive treatment for hepatitis-associated aplastic anemia may be safe during active hepatitis and alternative treatment except for hematopoietic stem cell transplantation.

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