Receptor tyrosine kinases are considered to play an important role for tumorigenesis. Among them, a class III receptor-type tyrosine kinase family, including FMS-like tyrosine kinase 3 (FLT3), stem cell factor receptor (KIT), and platelet-derived growth factor receptor (PDGFR), which is expressed on immature hemalopoiectic stem cells, plays an important role for cell growth, survival, differentiation, and migration. Recently, internal tandem duplication (ITD) and mutations of D835/I836 in the tyrosine kinase (TK) domain of the FLT3 gene have been reported in adult and pediatric acute myeloid leukemia (AML), and myelodysplastic syndrome (MDS), but not in acute lymphoblastic leukemia (ALL). The frequency and clinical significance of mutations of the FLT3, KIT, and PDGFRA genes are herereviewed in pediatric leukemias. Interestingly, FLT3 TK-mutations were found in about 20% of hyperdiploid ALL patients and infant ALL patients with MLL rearrangements. These ALL patients with mutations tended to have a poorer prognosis than those without the mutations. KIT mutations were found in 8 of 46 AML patients with t (8;21) out of 135 AML patients treated on the AML99 protocol. Mutations of PDGFRA gene were found in 2 of 114 AML patients in our study. These results suggested that mutations of the FLT3, KIT and PDGFRA genes may be one of the second hit mutations involved in the development of pediatric leukemia and are associated with specific chromosomal abnormalities. We also review here clinical significance of nucleophosmin and JAK genes which are associated with these tyrosine kinases. Recent progress of molecular targeted therapy against pediatric hematologic disorders wasalso reviewed.

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The MLL (Mixed-Lineage Leukemia) gene was originally identified at chromosomal 11q23 translocations developing acute leukemia, which occurs at high frequency in infantile and secondary leukemia. As a consequence of rearrangements of MLL, MLL is fused with one of more than 50 different partner genes to yield a diverse collection of MLL fusion oncoproteins. Normal MLL protein assembles into a chromatin-modifying transcriptional regulatory supercomplex to regulate epigenetic pathways including methylation of histone H3 lysine 4, and plays a nonredundant and essential role in definitive hematopoiesis through maintenance of appropriate upregulation of HOX genes associated with methylation of histone H3 at their locus. Meanwhile, oncogenic MLL fusion protein, where the menin binding motif and DNA methyltransferase homology region within a portion of MLL are essential for their oncogenic potential, leads to leukemogenesis through a transactivation domain or an oligomerization domain within a portion of the fusion partner. MLL fusion protein, which constitutionally lacks activity of histone methyltransferase, aberrantly upregulates HOX genes by direct binding of their promoter regions. Recently, we established a multi-step leukemogenesis model where MLL fusion protein and secondary genetic alteration (s) such as FLT3 mutants cooperate to induce acute leukemia with shorter latencies, in contrast to myeloproliferative disease with long latencies by MLL fusion protein alone. Further progress in the field will provide novel insights into molecular mechanisms of MLL-mediated leukemogenesis, and help us develop direct MLL-fusion targeted therapy.

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A 4-year-old boy with severe hemophilia A and high titer inhibitors was treated with anti-CD20 monoclonal antibody (rituximab) followed by plasma derived FVIII concentrate to induce immune tolerance. Rituximab was administered in 4 weekly doses, 375 mg/m², and FVIII concentrate (100 U/kg/dose) was begun at the time of the 3rd rituximab administration and continued 3 times per week for 6 months. The titer of inhibitors decreased from 141 BU/ml to 80 BU/ml without anamnestic response to FVIII concentrate during the first 4 months, but it remained about 80 BU/ml thereafter. In addition, a prolonged hypogammaglobulinemia and severe neutropenia were observed without serious infection. Rituximab may be beneficial for patients with severe hemophilia A and high titer inhibitors; however, it is necessary to investigate many issues such as the availability of rituximab therapy, the appropriate method of rituximab administration, the validity of immune tolerance induction therapy together with rituximab therapy, the safety and the economic utility.

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Infant cases with acute myeloid leukemia (AML) can be cured by combination chemotherapy. However, hematopoietic stem cell transplantation (SCT) is required in some refractory cases. We report a case of an infant with AML in which remission was successfully induced by donor lymphocyte infusion (DLI) against relapse after reducedintensity hematopoietic stem cell transplantation (RIST). In this case, we adopted RIST for the refractory disease in order to reduce treatment-related toxicities and late adverse effects, since he was an infant with AML in which alloreactive graft-versus-leukemia (GVL) effects were expected. Shortly after a transient remission following RIST, this case developed a recurrence. To induce GVL, we administered two courses of DLI, which resulted in complete reinduction of remission, suggesting that allo-reactive immune mechanism is effective for AML. Elevenmonths after DLI, the disease remained in remission, although the patient had fallen into bronchiolitis obliterans. This case implies a new therapeutic strategy for refractory infant AML, but further study is needed on this therapy.

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We report here a 14-year-old boy with acute lymphoblastic leukemia (ALL) who developed intussusception during induction therapy. He was admitted due to fever and anemia, and his white blood cell count was 16, 600/μl with 68% blasts. He was diagnosed as having B-precursor ALL, and his peripheral leukemic blasts disappeared after 1-week oral administration of prednisolone (PSL). After the third administration of vincristine (VCR), he complained of abdominal pain and thereafter a diagnosis of jejunojejunal intussusception was made by abdominal CT scan. Induction chemotherapy was immediately discontinued, and he was kept fasted under intravenous hyperalimentation and administration of antibiotics, H₂-blocker, and gabexate mesilate. Surgical treatment was not performed because of bone marrow suppression, severe coagulopathy due to administration of L-asparaginase, and underlying impaired wound healing due to administration of PSL. Abdominal pain gradually subsided and spontaneous remission of intussusception was confirmed by CT scan at day 11 after the onset. Subsequent intestinal contrast X-ray failed to identify any organic lesions possibly leading to intussusception. In the present case, impaired peristaltic movement of the intestine induced by VCR might play a central role in the development of intussusception, in which some minute lesions were possibly implicated as an apex.

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