2006 Fiscal Year Final Research Report Summary
Analysis of multi-step processes of leukemia-genesis in childhood leukemia.
| Project/Area Number |
17591024
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| Research Category |
Grant-in-Aid for Scientific Research (C)
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| Allocation Type | Single-year Grants |
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| Section | 一般 |
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| Research Field |
Hematology
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| Research Institution | Aichi Cancer Center Research Institute |
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Principal Investigator |
TSUZUKI Shinobu Aichi Cancer Center, Division of Molecular Medicine, Laboratory head, 遺伝子医療研究部, 室長 (00342965)
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| Project Period (FY) |
2005 – 2006
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| Keywords | TEL-AML1 / childhood leukemia / array-based CGH / isoform |
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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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[Journal Article] Genetic abnormalities involved in t(12;21) TEL-AMLl acute lymphoblastic leukemia : Analysis by means of array-based comparative genomic hybridization2007
Author(s)
Tsuzuki S, Karnan S, Horibe K, Matsumoto K, Kato K, Inukai T, Goi K, Sugita K, Nakazawa S, Kasugai Y, Ueda R, Seto M
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Journal Title
Description
「研究成果報告書概要(和文)」より
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[Journal Article] Genetic abnormalities involved in t(12;2l) TEL-AML1 acute lymphoblastic leukemia : Analysis by means of array-based comparative genomic hybridization2007
Author(s)
Tsuzuki S, Karnan S, Horibe K, Matsumoto K, Kato K, Inukai T, Goi K, Sugita K, Nakazawa S, Kasugai Y, Ueda R, Seto M
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Journal Title
Cancer Science (in press)
Description
「研究成果報告書概要(欧文)」より
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