2007 Fiscal Year Final Research Report Summary
Downregulation of PU.1 is required for myeloma cell growth
| Project/Area Number |
17591002
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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 | Kumamoto University |
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Principal Investigator |
OKUNO Yutaka Kumamoto University, Medicine, DEPARTMENT of Hematology, assistant of professor (80363539)
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| Co-Investigator(Kenkyū-buntansha) |
HATA Hiroyuki Kumamoto University of Medicine, DEPARTMENT of Hematology, 講師 (70271129)
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| Project Period (FY) |
2005 – 2007
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| Keywords | Multiple Myeloma / PU.1 / Methylation / Demethylation Agents / TRAIL / Apoptosis / IRF7 / p21 |
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| Research Abstract |
PU.1 is a transcription factor important for both myeloid and lymphoid development. Conditional knockout mice in which the levels of PU.1 were 20% of that of wild-type developed acute myeloid leukemia, T cell lymphoma, and a CLL-like disease. These findings strongly suggest that PU.1 has tumor suppressive activity in multiple hematopoietic lineages. Therefore we evaluated PU. 1 expression levels in myeloma cells, and found that PU.1 is downregulated in a majority of multiple myeloma cell lines and freshly isolated CD138 positive myeloma cells from certain number of myeloma patients. Based on their PU.1 expression levels, we divided the myeloma patients into two groups, namely PU.1 high and PU.1 low-to-negative. The PU.1 low-to-negative patients had a significantly poorer prognosis than the PU.1 high patients. To elucidate the mechanisms of downregulation of PU.1, we performed epigenetic analysis of the promoter region and the -17 kb upstream region that is conserved among mammalians an
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d important for proper expression of PU.1. The -17 kb upstream region was highly methylated in 3 of 4 PU.1 negative myeloma cell lines, while the promoter region was also methylated to various levels in all five myeloma cell lines including one PU.1 positive cell line. These data suggested that the downregulation of PU.1 in myeloma cell lines might be dependent on the methylation of both regulatory regions of PU.1 gene, especially the -17 kb upstream region. In addition, tet-off inducible exogenous expression of PU.1 in PU.1 negative myeloma cell lines induced cell growth arrest and apoptosis. We subsequently evaluated the mechanisms of cell growth arrest and apoptosis of myeloma cell lines induced by PU.1. Among apoptosis-related genes, we identified that TRAIL was upregulated after PU.1 induction. To evaluate the effect of upregulation of TRAIL, we stably introduced siRNA for TRAIL into myeloma cell lines expressing PU.1, and we found that apoptosis of these cells was partially suppressed by siRNA for TRAIL, suggesting that apoptosis of myeloma cells induced by PU.1 might be at least partially due to TRAIL upregulation. Less
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[Journal Article] 2008.PU.1 is a major downstream target of AML1(RUNX1) in adult mouse hematopoiesis2007
Author(s)
Huang, G. ; Zhang, P. ; Hirai, H. ; Elf, S. ; Yan, X. ; Chen, Z. ; Koschmieder, S. ; Okuno, Y. ; Dayaram, T. ; Growney, .J.D, ; Shivdasani, R. A. ; Gilliland D. G. : Speck, N. A ; Nimer, SD. ; Tenen, D. G ; Kikukawa, Y. ; H.
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Journal Title
Nat Genet 2011
Pages: 40 : 51-60
Description
「研究成果報告書概要(欧文)」より
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[Journal Article] Down-regulation of PU.1 by Methylation of Distal Regulatory Elements and the Promoter Is Required for Myeloma Cell Growth2007
Author(s)
Tatetsu, H, Ueno, S, Hata H., Yamada, Takeya, M. Mitsuya, H., Temen, D.G., Okuno, Y
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Journal Title
Cancer Res 67
Pages: 5328-5336
Description
「研究成果報告書概要(欧文)」より
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[Journal Article] Activation of the endoplasmic reticulum stress pathway is associated with survival of myeloma cells2006
Author(s)
Nakamura, M. Gotoh, T. Okuno, Y., Tatetsu, H., Sonoki, T., Uneda, S., Mori, M., Mitsuya, H., Hata, H
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Journal Title
Leuk Lymphoma 47
Pages: 531-539
Description
「研究成果報告書概要(欧文)」より
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[Journal Article] Dehydroxymethylepoxyquinomicin, a novel nuclear factor{kappa}B inhibitor, induces apoptosis in multiple myeloma cells in an I{kappa}B{alpha}-independent manner.2005
Author(s)
Tatetsu, H., Okuno, Y., Nakamura, M., Matsuno, F., Sonoki, T., Taniguchi, I., Uneda, S., Umezawa, K., Mitsuya, H., Hata, H
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Journal Title
Mol Cancer Ther 4
Pages: 1114-1120
Description
「研究成果報告書概要(欧文)」より
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[Journal Article] Potential autoregulation of transcription factor PU.l by an upstream regulatory element.2005
Author(s)
Okuno, Y., Huang, G., Rosenbauer, F., Evans, E. K., Radomska, H, S Iwasaki, H., Skashi, K., Moreau-Gachelin, F., Li, Y., Zhang, P., et. al.
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Journal Title
Mol Cell Biol 25
Pages: 2832-2845
Description
「研究成果報告書概要(欧文)」より
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[Presentation] Microarray analysis of PU.l-induced growth arrest and apoptosis of myeloma cell lines.2007
Author(s)
Shikiko, Ueno, Hiro, Tatetsu, Naoko, Harada, Hiroyuki, Hata, Tadafumi, lino, Hiroaki, Niiro, Koichi, Akashi, G., Daniel, Tenen, Hiroaki, Mitsuya, Yutaka, Okuno
Organizer
American Society of Hemetology, Sunday
Place of Presentation
Georgia World Congress Center Atlanta Georgia
Year and Date
2007-12-09
Description
「研究成果報告書概要(欧文)」より
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[Presentation] PU.1 is downregulated in a subset of multiple myeloma by the methylation of its "17 kb upstream regulatory region and the promoter.2006
Author(s)
Yutaka, Okuno, Hiro, Tatetsu, Shikiko, Ueno, Hiroyuki, Hata, Yasuhiro, Yamada, Motohiro, Takeya, Tadafumi, lino, Koichi, Akashi, Daniel, G., Tenen, Hiroaki, Mitsuya
Organizer
American Society of Hemetology
Place of Presentation
Orange County Convention Center Orlando, Florida
Year and Date
20061209-12
Description
「研究成果報告書概要(欧文)」より
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[Presentation] Downregulation of PU. l is required for subtype of multiple myeloma.2005
Author(s)
Hiro, Tatetsu, Hiroyuki, Hata, Yasuhiro, Yamada, Hiroaki, Mitsuya, Yutaka, Okun
Organizer
American Society of Hemetology
Place of Presentation
Georgia World Congress Center Atlanta, Georgia
Year and Date
20051210-13
Description
「研究成果報告書概要(欧文)」より
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