| Budget Amount *help |
¥8,600,000 (Direct Cost: ¥8,600,000)
Fiscal Year 2005: ¥2,400,000 (Direct Cost: ¥2,400,000)
Fiscal Year 2004: ¥2,400,000 (Direct Cost: ¥2,400,000)
Fiscal Year 2003: ¥3,800,000 (Direct Cost: ¥3,800,000)
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| Research Abstract |
We analyzed a complex translocation involving chromosomes 7, 11, 19 and 22 in infant acute monocytic leukemia, and identified that the MLL gene on 11q23 was fused to the unconventional myosin type 1F, MYO1F, gene on 19p13.2-13.3. The MYO1F gene bears no homology with the partner genes of MLL previously described, therefore, this finding would provide new insights into leukemogenesis associated with MLL.
We next performed mutational analysis of FLT3 genes in childhood acute lymphoblastic leukemia (ALL), and found FLT3-D835/I836 mutations in 8(18.2%) of 44 infants with ALL with MLL rearrangements. In mouse model, MLL-SEPT6 induced myeloproliferative disease with long latency, but not acute leukemia. We developed in vitro and in vivo model systems of leukemogenesis by MLL fusion proteins, where activated FMS-like receptor tyrosine kinase 3(FLT3) together with MLL-SEPT6 not only transformed hematopoietic progenitors in vitro but also induced acute biphenotypic or myeloid leukemia with short latency in vivo. These findings showed direct evidence for a multistep leukemogenesis mediated by MLL fusion proteins and may be applicable to development of direct MLL fusion-targeted therapy.
We also performed mutational analysis of KIT and FLT3 genes in childhood acute myeloid leukemia (AML) with t(8;21), and found the kinase domain mutations of the KIT gene in 8 (17.4%) of 46 patients. FLT3 internal tandem duplication was found in only 2 (4.3%) patients. Significant differences between patients with or without KIT mutations were observed in the 4-year overall survival (50.0% versus 97.4%, P<0.001), disease-free survival (37.5% versus 94.7%, P<0.001) and relapse rate (47.0% versus 2.7%, P<0.001). Although patients with t(8;21)-AML are generally considered to have a good prognosis, these results suggested that KIT mutations are strongly associated with a poor prognosis in pediatric t(8;21)-AML.
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