白血病細胞における細胞骨格・転写・細胞周期の制御異常

• Project/Area Number: 13216005
• Research Category: Grant-in-Aid for Scientific Research on Priority Areas
• Allocation Type: Single-year Grants
• Review Section: Biological Sciences
• Research Institution: Tohoku University
• Principal Investigator: 佐竹 正延 東北大学, 加齢医学研究所, 教授 (50178688)
• Co-Investigator(Kenkyū-buntansha): 仙波 憲太郎 東京大学, 医科学研究所, 助教授 (70206663)
• Project Period (FY): 2001 – 2004
• Project Status: Completed (Fiscal Year 2004)
• Budget Amount: ¥62,200,000 (Direct Cost: ¥62,200,000); Fiscal Year 2004: ¥14,600,000 (Direct Cost: ¥14,600,000); Fiscal Year 2003: ¥14,600,000 (Direct Cost: ¥14,600,000); Fiscal Year 2002: ¥16,000,000 (Direct Cost: ¥16,000,000); Fiscal Year 2001: ¥17,000,000 (Direct Cost: ¥17,000,000)
• Keywords: 白血病 / 遺伝子発現 / キメラ遺伝子 / RunX / WT1 / 転写因子 / マイクロアレイ / 細胞骨格 / 転写制御 / PEBP2β / フィラミン / BAL1 / 細胞周期

Research Abstract

t(8;21)転座、inv(16)逆位はそれぞれ、Runx1-MTG8及びPEBP2beta-SMMHCキメラ遺伝子を生成する。AMLとしては各々、M2及びM4サブタイプの形態学的表現型を示す。上記の2つ、及びその他の染色体異常を伴うAML、合計54症例を用いて遺伝子発現プロファイリングを実施した。コントロールを適切に取ることにより、lineage/stageに依存せずに発現変動を示すと考えられる遺伝子群を抽出した。t(8;21)とinv(16)に共通して発現上昇する遺伝子群も存在したが、t(8;21)特異的に又はinv(16)特異的に発現上昇する遺伝子群も検出することができた。2つのキメラ蛋白は、正常のRunx1/PEBP2beta転写因子機能に対してドミナント・ネガティブに作用することが知られているが、それのみによって2つの型の白血病細胞における遺伝子発現パタンを説明できるものではないことが示唆された。
WT1の4種類のアイソフォームおよびDSRCT (desmoplastic small round cell tumor)の発症に関わるとされるEWS-WT1キメラがん遺伝子の発現細胞からRNAを調製し、20,000遺伝子を網羅するマイクロアレイを用いて発現プロファイルを作成した。これにより、WT1のアイソフォームとEWS-WT1の各々に特異的に誘導される遺伝子群を同定した。EWS-WT1発現細胞では、血管新生抑制因子BAI-1と接着と運動にかかわるTALLA-1に着目して解析を進めた。Jurkat細胞において、抗TALLA1抗体は細胞どうしの接着性を著しく促進させること、抗CD3抗体と協調的にERKのリン酸化を促進することを示した。

Research Products

• [Journal Article] Filamin A-Bound PEBP2β/CBFβ is retained in the cytoplas and prevented from functioning as a partner of the Runx1 transcription factor. (2005)
  • Author(s): Yoshida, N. et al.
  • Journal Title: Mol.Cell Biol. 25 Pages: 1003-1012
• [Journal Article] Over-expression of the Runx3 transcription factor increases the proportion of mature thymocytes of the CD8 single positive lineage. (2005)
  • Author(s): Kohu, K. et al.
  • Journal Title: J.Immunol. 174 Pages: 2627-2636
• [Journal Article] Gene expression profiling identifies a set of transcripts that are up-regulated in human testicular seminoma. (2004)
  • Author(s): Yamada, S. et al.
  • Journal Title: DNA Res. 11 Pages: 335-344
• [Journal Article] Identification of transcripts expressed preferentially in hemocytes of Ciona intestinalis that can be used as molecular markers. (2004)
  • Author(s): Wakoh, T. et al.
  • Journal Title: DNA Res. 11 Pages: 345-352
• [Journal Article] A novel GTPase-activating protein for ARF6 directly interacts with clathrin and regulates the clathrin-dependent endocytosis.
  • Author(s): Tanabe, K. et al.
  • Journal Title: Mol.Biol.Cell (in press)
• [Journal Article] Dual functions of Runx proteins for re-activating CD8 and silencing CD4 at the commitment process into CD8 thymocytes.
  • Author(s): Sato, T. et al.
  • Journal Title: Immunity (in press)
• [Publications] Komine, O. et al.: "The Runx1 transcription factor inhibits the differentiation of naive CD4+ T cells into the Th2 lineage by repressing GATA3 expression."J.Exp.Med.. 198. 51-61 (2003)
• [Publications] Sato, T. et al.: "Requirement of transcription factor AML1 in proliferation of developing thymocytes."Immunol.Lett.. 89. 39-46 (2003)
• [Publications] Ehlers, M. et al.: "Morpholino antisense oligonucleotide-mediated gene knockdown during thymocyte development reveals role for Runx3 transcription factor in CD4 silencing during development of CD4-/CD8+ thymocytes."J.Immunol.. 17. 3594-3604 (2003)
• [Publications] Ito, E.et al.: "A Tetraspanin-Family Protein, T-Cell Acute Lymphoblastic Leukemia-Associated Antigen 1, Is induced by the Ewing's Sarcoma-Wilms' Tumor 1 Fusion Protein of Desmoplastic Small Round-Cell Tumor."Am.J.Pathol.. 163. 2165-2172 (2003)
• [Publications] Matsuzawa-Watanabe, Y. et al.: "Transcriptional activity of testis-determining factor SRY is modulated by the Wilms' tumor I gene product, WT1."Oncogene. 22. 7900-7904 (2003)
• [Publications] Ishikawa, K. et al.: "Cloning and characterization of Xenopus laevis drg2, a member of the developmentally regulated GTP-binding protein subfamily."Gene. 322. 105-112 (2003)
• [Publications] Watanabe, T. et al.: "SEK1/MKK4-mediated SAPK/JNK signaling participates in embryonic hepatoblast proliferation via a pathway different from NF-kB-induced anti-apoptosis"Dev.Biol.. 250. 332-347 (2002)
• [Publications] Yoshida, C.A. et al.: "Core-binding factor β interacts with Runx2 and is required for skeletal development"Nature Genet.. 32. 633-638 (2002)
• [Publications] Dehal, P. et al.: "The draft genome of Ciona intestinalis : Insights into chordate and vertebrate origins"Science. 298. 2157-2167 (2002)
• [Publications] Terajima, D. et al.: "Identification of candidate genes encoding the core components of the cell death machinery in the Ciona intestinalis genome"Cell Death Different. (in press). (2003)
• [Publications] Shida, K. et al.: "Hemocytes of Ciona intestinalis express multiple genes involved in innate immune host defense"Biochem.Biophys.Res.Com.. (in press). (2003)
• [Publications] Takatsuna, H. et al.: "Identification of TIFA as an adapter protein that links TRAF6 to IRAK-1 in IL-1 receptor signaling"J.Biol.Chem.. (in press). (2003)
• [Publications] Yokomizo, T.et al.: "Requirement of Runx1/AML1/PEBP2α B for the generation of hematopoietic cells from endothelial cells"Genes to Cells. 6. 13-23 (2001)
• [Publications] Hayashi, K.et al.: "Overexpression of AML1 transcription factor drives thymocytes into the CD8 single positive lineage"J.Immunol.. 167. 4967-4965 (2001)
• [Publications] Nakazawa, T.et al.: "Characterization of Fyn-mediated tyrosine phosphorylation sites on GluR ε 2 (NR2B) subunit of the N-methyl-D-aspartate receptor"J.Biol.Chem.. 276. 693-699 (2001)
• [Publications] Yamochi, T.et al.: "ik3-1/Gables is a substrate for cyclin-dependent kinase 3 cdk 3)"Eur.J.Biochem.. 268. 6076-6082 (2001)