| Budget Amount *help |
¥3,500,000 (Direct Cost: ¥3,500,000)
Fiscal Year 2006: ¥1,300,000 (Direct Cost: ¥1,300,000)
Fiscal Year 2005: ¥2,200,000 (Direct Cost: ¥2,200,000)
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| Research Abstract |
(1)TEL-AML1 fusion gene, generated by t(12 ; 21) translocation, is the commonest abnormality in childhood leukemia, and is exclusively associated with B cell leukemia. We have addressed the mechanism whereby the translocation generates the leukemia, using mouse model. Although we are able to see the fusion is able to block B cell differentiation, and expand cell population, mice did not develop leukemia. We therefore next searched for additional genetic abnormalities which could be linked leukemia-genesis. To this end, we analyzed clinical leukemia samples and cell lines by the use of array-CGH method. We then found that all the cases had at least 2 genetic abnormalities, in addition to TEL-AML1 translocation. Among these, loss of TEL on the untranslocated allele was most commonly found, followed by losses of genes involved in cell cycle regulation, such as BTG1, p16INK4a/ARF. Enforced expressions of the gene products found lost in Reh, a TEL-AML1 cell line, inhibited the cell proliferation. These findings suggest the losses of the genes may partly account for the leukemia-genesis.
(2)Evidence is accumulating that a specific isoform of a given transcription factor is associated with leukemia. There are two isoforms in Runx1/AML1 transcription factor, but their differential roles and possible association with leukemia-genesis have not been well explored. We found that the short isoform, AML1a, is expressed exclusively in CD34-positive immature stem/progenitors among human cord blood cells. We therefore next transduced mouse/human hematopoietic cells using retrovirus/lentivirus to see if the expression of AML1a has any impact on stem/progenitor activities both in vitro and in vivo. We then found that AML1a expression confers cells self-renewal activities, growth advantage, higher engraftment potential. We concluded that the blood cell expansion thus achieved is more likely to obtain additional genetic hits, and thus leading to leukemia.
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