転写因子PEBP2と白血病発症の機序

• 研究課題/領域番号: 09253220
• 研究種目: 重点領域研究
• 配分区分: 補助金
• 研究機関: 京都大学
• 研究代表者: 伊藤 嘉明 京都大学, ウイルス研究所, 教授 (80004612)
• 研究分担者: 丸山 光生 京都大学, ウイルス研究所, 助手 (00212225) ; 菅野 智彦 京都大学, ウイルス研究所, 助手 (10273525)
• 研究期間 (年度): 1994 – 1999
• 研究課題ステータス: 完了 (2000年度)
• 配分額: 75,000千円 (直接経費: 75,000千円); 1999年度: 30,000千円 (直接経費: 30,000千円); 1998年度: 30,000千円 (直接経費: 30,000千円); 1997年度: 15,000千円 (直接経費: 15,000千円)
• キーワード: PEBP2 / Runx1 / Runx2 / Runx3 / AML1 / 白血病 / 消化管 / 鎖骨頭がい異形成症 / 急性骨髄性白血病 / 点突然変異 / ヘテロ変異体 / 血管内皮細胞 / G-CSF / FPD / AML / 転写因子 / CBF / 発がん機構 / キメラ遺伝子 / 転写制御機構 / ETO(MTG8) / 32Dc13

研究概要

PEBP2はα、β、2つのサブユニットからなる。αサブユニットをコードする遺伝子は哺乳類に3種ありRunx1/AML1,Runx2/Cbfa1,Runx3/PEBP2αCと呼ばれる。
我々はRunx1は成体型造血に必須で血管内皮細胞から造血幹細胞が形成される過程で機能する事を明らかにした。一方Runx1はもっとも高頻度で白血病に伴う染色体転座のターゲットになっているが、我々は散発性に機能消失型点突然変異のある白血病を検出し報告した。家族性のものが外国のグループより発表され、Familial platelet disorder with predisposition to acute myeloid leukemia(FPD-AML)と呼ばれ新しい病型であることが示された。Runx1のヘテロ変異体マウスはFPD-AMLのモデルとなり、Runx1のhaploinsufficiencyが白血病原性を持つとするデータが蓄積されている。
Runx2は骨芽細胞の成熟に必須で、骨組織形成のマスターレギュレーターである。Runx2のhaploinsufficiencyでヒトの骨疾患、鎖骨頭がい異形成症(cleidocranial dyplasia、CCD)がおこる。我々はRunxファミリーはTGF-β及びMBPのシグナルで制御される事を報告した。更にCCDはRunx2の変異のためBMPのシグナル伝達が阻害されるために起こる事を示した。
Runx3は消化管、血液細胞、神経系等で発現している。Runx3ノックアウトマウスでは幽門腺分化遅延、体部上皮細胞層hyperplasia、上皮細胞のアポトーシスの著しい減少がみられる。これらの所見より、ヒト胃がんの発生におけるRunx3の関与が考えられた。

研究成果

• [文献書誌] Sakakura et al.: "Growth inhibition and induction of differentiation of t(8 ; 21) acute myeloid leukemia cells by the DNA-binding domain of PEBP2 and the AML1/MTG8(ETO)-specific antisense oligonucleotide"Proc.Natl.Acad.Sci.USA. 91. 11723-11727 (1994)
  • 説明: 「研究成果報告書概要(和文)」より
• [文献書誌] Lu et al.: "Subcellular localization of the α and β subunits of the acute myeloid leukemia-linked tanscription factor PEBP2/CBF."Mol.Cell.Biol.. 15. 1651-1661 (1995)
  • 説明: 「研究成果報告書概要(和文)」より
• [文献書誌] Osato et al.: "Biallelic and heterozygous point mutations in the Runt domain of the AML1/PEBP2αB gene associated with myeloblastic leukemias."Blood. 93. 1817-1824 (1999)
  • 説明: 「研究成果報告書概要(和文)」より
• [文献書誌] Kim et al.: "Mutual activation of Ets-1 and AML1 DNA binding by direct interaction of their autoinhibitory domains."EMBO J.. 18. 1609-1620 (1999)
  • 説明: 「研究成果報告書概要(和文)」より
• [文献書誌] Nagata et al.: "Immunoglobulin motif DNA recognition and heterodimerization for the PEBP2/CBF Runt-domain."Nature Struct.Biol.. 6. 615-619 (1999)
  • 説明: 「研究成果報告書概要(和文)」より
• [文献書誌] Werner et al.: "Runt-domain take the lead in hematopoiesis and osteogenesis."Nature Medicine. 5. 1356-1357 (1999)
  • 説明: 「研究成果報告書概要(和文)」より
• [文献書誌] Sakakura et al.: "Growth inhibition and induction of differentiation of t (8 : 21) acute myeloid leukemia cells by the DNA-binding domain of PEBP2 and the AML1/MTG8 (ETO) -specific antisense oligonucleotide"Proc.Natl.Acad.Sci.USA. 91. 11723-11727 (1994)
  • 説明: 「研究成果報告書概要(欧文)」より
• [文献書誌] Lu et al.: "Subcellular localization of the αand βsubunits of the acute myeloid leukemia-linked tanscription factor PEBP2/CBF."Mol.Cell.Biol.. 15. 1651-1661 (1995)
  • 説明: 「研究成果報告書概要(欧文)」より
• [文献書誌] Osato et al.: "Biallelic and heterozygous point mutations in the Runt domain of the AML1/PEBP2αβ gene associated with myeloblastic leukemias."Blood. 93. 1817-1824 (1999)
  • 説明: 「研究成果報告書概要(欧文)」より
• [文献書誌] Kim et al.: "Mutual activation of Ets-1 and AML1 DNA binding by direct interaction of their autoinhibitory domains."EMBO J.. 18. 1609-1620 (1999)
  • 説明: 「研究成果報告書概要(欧文)」より
• [文献書誌] Nagata et al.: "Mutual activation of Ets-1 and AML1 DNA binding by direct interaction of their autoinhibitory domains."Nature Struct.Biol.. 6. 615-619 (1999)
  • 説明: 「研究成果報告書概要(欧文)」より
• [文献書誌] Werner et al.: "Runt-domain take the lead in hematopoiesis and osteogenesis."Nature Medicine. 5. 1356-1357 (1999)
  • 説明: 「研究成果報告書概要(欧文)」より
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• [文献書誌] Zhang, Y. -W.: "PEBP2αA/CBFA1 mutations in Japanese Cleidocranial Dysplasia patients"Gene. (in press).
• [文献書誌] Hanai, J.: "Interaction and functional cooperation of PEBP2/CBF with Smads Synergistic induction of the immunoglobulin germline Cα promoter"J. Biol. Chem.. 274. 31577-31582 (1999)
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• [文献書誌] Koike, K.: "Survey of hepatitis B virus co-infection in hepatitis C virus-infected patients suffering from chronic hepatitis and hepatocellular carcinoma in Japan (LETTER TO THE EDITOR)"Jpn. J. Cancer Res.. 90. 1270-1272 (1999)
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• [文献書誌] Kohzaki, H.: "Context dependent modulation of the replication activity of Saccharomyces cerevcisiae autonomously replicating sequences by transcription factors"Mol. Cell. Biol.. 19. 7428-7435 (1999)
• [文献書誌] Ogihara, H.: "Synergy of PEBP2/CBF with mi transcription factor (MITF) for transactivation of mouse mast cell protease 6 gene"Oncogene. 18. 4632-4639 (1999)
• [文献書誌] Osato, M.: "BiaHelic and heterozygous point mutations in the Runt domain of the AML1/PEBP2αB gene associated with myeloblastic leukemias"Blood. 93. 1817-1824 (1999)
• [文献書誌] Kohzaki, H.: "Block of granulocytic differentiation of 32Dcl3 cells by AML1/ETO(MTG8) but not by highly expressed Bcl-2"Oncogene. 18. 4055-4062 (1999)
• [文献書誌] Morii, E.: "Identification of the region of transcription factor which is responsible for the Synergy with PEBP2/CBF"Biochem. Biophys. Res. Commu.. 261. 53-57 (1999)
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• [文献書誌] Tanaka,Y.: "The chimeric protein,PEBP2β/CBFβ-S,SMMHC,disorganizes cytoplasmic stress fibers and inhibits transcriptional activation." Oncogene. 17. 699-708 (1998)
• [文献書誌] Kanno T.: "Cytoplasmic sequestration of the polyomavirus enhapcer binding protein 2(PEBP2)/core binding factor a(CBFa)subunit by the leukemia-related PEBP2/CBFβーSMMHC fusion protein inhibits PEBP2/CBF-Mediated transactivation." Mol.Cell.Biol.18. 4252-4261 (1998)
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• [文献書誌] Tsuji,K.: "Expression of the PEBP2αA/AML3/CBFA1 genes is Regulated by BMP4/7 heterodimer and its overexpression suppresses type I collagen and osteocalcin gene expression in osteoblastic and nonosteoblastic mesenchymal cells." Bone. 22. 87-92 (1998)
• [文献書誌] Ji,C.: "CBFa(AML/PEBP2)-related elements in the TGF-b type I receptor promoter and expression with osteoblast differentiation." J.Cell.Biochem.69. 353-363 (1998)
• [文献書誌] Sato,M.: "Transcriptional regulation of osteopontin gene in vivo by PEBP2αA/CBF and ETS1 in the skeletal tissues." Oncogene. 17. 1517-1525 (1998)
• [文献書誌] Kanno,T.: "Intrinsic transcriptional activation/inhibition domains of the PEBP2/CBF α subunit revealed in the presence of the β subunit." Mol.Cell.Biol.18. 2444-2454 (1999)
• [文献書誌] Ahn,M.-Y.: "Negative regulation of granulocytic differentiation in the myeloid precursor cell line 32Dc13 by car-2,a mammalian homolog of Drosophila seven-up,and a chumeric leukemogenic gene,AML1/ETO(MTG8)." Proc.Natl.Acad.Sci.USA. 95. 1812-1817 (1998)
• [文献書誌] Kanno T.: "Infrinsic transcriptional activation/inhibition domains of the PEBP2/CBF α subunit revealed in the presence of the β subunit." Mo1.Cell.Biol.in press. (1998)
• [文献書誌] Ahn M-Y.: "Negative regulation of granulocytic defferentiation in the myeloid precursor cell line 32Dc13 by car-2,a mammalian homolog of Drosophila seven-up,and a chimeric leukemogenic gene,AMLI/ETO (MTG8)." Proc.Natl.Acad.Sci.USA. 95. 1812-1817 (1998)
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• [文献書誌] Tanaka Y.: "The protooncogche product,PEBP2β/CBFβ,is mainly located in the cytoplasm and has an affinity with cytoskeletal structurs." Oncogene. 15. 677-683 (1997)
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