Many fusion genes have been isolated from genomic breakpoints of chromosome translocations specifically observed in hematopoietic malignancies. Most of the fusion genes involve functionally important key regulatory genes involved in the development of hematopoietic cells, such as transcription factors or protein tyrosine kinases. The loss of functional domain and/or gain of another functional domain from the translocation partner gene often modulate the normal function of a key regulator protein. This abnormally formed fusion protein has the potential to inhibit the differentiation of hematopoietic cells, to promote proliferation, and/or to inhibit apoptotic cell death, finally leading to overt leukemia. The genetic and functional analyses of leukemogenic fusion genes are essential not only to elucidate leukemogenic mechanisms, but also to discover new methods of treatment and ultimately the prevention of leukemia. In this review the current molecular bases of fusion gene formation and current clinical applications are discussed.

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We treated six patients with childhood acute lymphoblastic leukemia (ALL) and Down syndrome (DS) during the period from 1987 to 1997. The median age at diagnosis was three years and eight months. The median white blood cell count was16, 800/μl. The analysis of immunophenotypes of the blasts revealed that five had pre-B cell type and one had biphenotypic ALL. Three were treated by Tokai Pediatric Oncology protocol, one by JACLS-ALL 97 protocol and the other two by multidrug combination therapy, including CHOP. Although all six patients had achieved complete remission, two relapsed. One patient died of serious bacterial infection after relapse, and one received autologous bone marrow transplantation with a preconditioning regimen using L-PAM and TBI, resulting in long-term survival. Three patients remain in the first remission. One died of liver dysfunction because of methotrexate (MTX) during maintenance therapy with no evidence of recurrence. Plasma concentrations after high-dose MTX (3g/m²) therapy were higher in patients with DS than in patients without it, but there was no statistical significance. The concentrations that followed after reduced MTX (1-2 g/m²) therapy were almost equal among those with DS and those with MTX (3g/m²) without DS.

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We performed flow cytometric analysis by using the CD45/SSC (CD45^low/SSC^low) gating method in 5 bone marrow (BM) samples with low percentages of blasts at the disease onset. The surface marker profiles in 4 cases (ALL 2, MDS 1, NHL 1) at the onset proved almost identical to those at the final diagnosis. In the last case, however, the patient was diagnosed as having neuroblastoma (CD45 negative) despite a B-cell precursor phenotype of BM cells gated by this method. To address issues on diagnostic disagreement in this case, we examined the surface markers of the BM populating gated by this method in 10 children with malignancy in complete remission. About 10% of the BM cells were gated to the CD45low/SSClow population, and their markers were CD10^bright/CD19^bright/HLADR^bright/CD20^dim/CD33^dim/CD34^dim, which was consistent with the phenotype of the B-cell precursors. Although the surface marker analysis using the CD45/SSC gating method is useful for the diagnosis of pediatric hematological malignancies, the results should be carefully interpreted with an understanding of the usefulness and the pitfalls of this methodology.

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We investigated the long-term performance status of childhood recipients by means of a questionnaire because the quality of life in the long-term survivors following allogeneic hematopoietic stem cell transplantation remains unclear. Six cases of. secondary malignancy were reported. T-non Hodgkin lymphoma or myelodysplastic syndrome developed in the early period following transplantation and solid tumors such as brain tumors or lingual tumors in the late period. Chronic mucositis caused by the graft-versus-host disease (GVHD) might be involved in the carcinogenesis of the lingual tumor that occurred in a case of Fanconi anemia. Severe GVHD caused by HLA disparity and the administration of antithymocyte globulin were risk factors for the development of EB virus-associated lymphoproliferative disorder (EB-LPD). The deterioration of performance status caused by the development of chronic GVHD was reported in 46 cases. The development of bronchiolitis obliterans, arthropathy because of chronic GVHD of the skin, and encephalopathy related to the immunosuppressants were major sequels that influenced long-term performance status in pediatric survivors. It seems that the Karnofsky score used in this study may not reflect the patient's performance status because there is a discrepancy between the reported scores and symptoms. A new score system must be established to evaluate the quality of life from various aspects in long-term pediatric survivors.

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We report a case of childhood acute lymphoblastic leukemia (ALL) presenting with bone marrow necrosis. A 4-year-old girl complained of severe leg pain and fever. Laboratory data revealed pancytopenia and a high level of serum LDH, and bone marrow aspiration showed only necrotic marrow. About one month later, the necrotic materials had disappeared and been replaced by lymphoblasts of L I morphology and B-precursor immunophenotype. She was successfully induced to complete remission by standard chemotherapy and has been in continuous remission for 23 months after the diagnosis of ALL. Bone marrow necrosis is rarely diagnosed during life and is generally considered a poor prognostic sign. However, when it occurs at presentation, which is most often observed in children with ALL, it may not be associated with poor prognosis.

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We report 2 cases with severe hemophilia A that developed inhibitors and acquired immune tolerance to them after replacing a different origin for factor VIII. In the first case, a regular infusion of recombinant factor VIII (r-FVIII) was applied after a diagnosis of hemophilia A. The inhibitor appeared within the first year after the start of regular infusions of r-FVIII. The titer of the inhibitor had decreased following immune tolerance induction (ITI) therapy with plasma-derived factor VIII (pd-FVIII). On the other hand, in the second case, the inhibitor appeared after regular infusions of pd-FVIII. The infusions of pd-FVIII had been stopped and the inhibitor titer declined ; the infusions of r-FVIII had been started and the inhibitor disappeared. These cases indicate that ITI is possible even when factor VIII of a different origin is used.

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