2004 Fiscal Year Final Research Report Summary
Analyse of oncogenic function of the MLL/AF4 gene
| Project/Area Number |
15591029
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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 | Nippon Medical School |
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Principal Investigator |
DAN Kazuo Nippon Medical School, Hematology/oncology, Dept of Int.Med., 大学院・医学研究科, 教授 (90142538)
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| Co-Investigator(Kenkyū-buntansha) |
INOKUCHI Koiti Nippon Medical School, Hematology/oncology, Dept of Int.Med., 医学部, 助教授 (10203267)
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| Project Period (FY) |
2003 – 2004
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| Keywords | MLL / AF4 / Transgenic mouse / 32D / leukemogenesis / アポトーシス |
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| Research Abstract |
Acute lymphoblastic leukemia(ALL) expressing MLL-AF4,the fusion product of t(4;11)(q21;q23), respond poorly to chemotherapy and have poor prognosis. MLL was required in normal hematopoietic proliferation and differentiation through Hox gene regulation. AF4 is a serine/proline rich nuclear protein with transcriptional activation domain and plays an important role in B and T lymphopoiesis. The MLL-AF4 fusion protein preserves the AT-hook and methyltransferase domains of MLL and the GTP binding, and nuclear localization regions of AF4. Previous in vitro and vivo study predicted that leukemia-specific chimeric proteins in 11q23 leukemia including MLL-AF4 would associated with leukemogenesis, although the mechanisms still unknown. In the present study, we successfully established a cell line expressing MLL-AF4 from proB ALL patients with t(4;11)(q21;q23). This cell line expressed CD10^- CD15^+ CD19^+ phenotype and overexpressed c-myc by duplication chromosome 8. We have also succeeded to clone cDNA of MLL-AF4 from this cell line, and used it to confirm leukemogenetic mechanisms. Murine IL3 dependent cell line 32Dc was transduced with lentiviral vector(pCL20c Mp) encoding human MLL-AF4 cDNA. After confirming MLL-AF4 expression by RT-PCR, each clone was isolated by limiting dilution. First we examined growth profile under IL3 deprivation in 32D cell line. 32Dc without MLL-AF4 did not grow and demonstrated apoptotic cell death under IL3 deprivation, by contrast MLL-AF4 transduced cell lines temporally grew and tended to show anti-apoptotic effect. Next we are using a 32Dc cell line showing myeloid differentiation in response to granulocyte colony stimulating factor (G-CSF) and we will analyze inhibition of differentiation in MLL-AF4 transfected 32D cell line. These results and ongoing studies will clarify that MLL-AF4 plays an important role in leukemogenesis.
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[Journal Article] Novel transgenic mice expressing P230 Bcr/Abl developed myeloproliferative disorder : longer disease latency, thrombocytosis and mild leukocytosis2003
Author(s)
Koiti Inokuchi, Kazuo Dan, Miyuki Takatori, Hidemasa Takahuji, Naoya Uchida, Mitsuharu Inami, Koichi Miyake, Hiroaki Honda, Hisamaru Hirai, Takashi Shimada
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Journal Title
Blood 102(1)
Pages: 320-323
Description
「研究成果報告書概要(欧文)」より
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