1999 Fiscal Year Annual Research Report

転写因子PEBP2の構造異常による白血病発症の機序

Research Project

Project/Area Number	09253220
Research Institution	Kyoto University
Principal Investigator	伊藤嘉明京都大学, ウイルス研究所, 教授 (80004612)
Co-Investigator(Kenkyū-buntansha)	菅野智彦京都大学, ウイルス研究所, 助手 (10273525)
Keywords	急性骨髄性白血病 / AML1 / 点突然変異 / ヘテロ変異体 / 血管内皮細胞 / G-CSF / FPD / AML
Research Abstract	AML1/PEBP2αB遺伝子は急性白血病の約30%の原因になっていると考えられている。従来白血病はその病型に特異的な染色体転座が観察されるところから、転座によって生じるキメラ遺伝子の構造と機能に研究の力点がおかれてきた。我々も含め多くの研究グループの成果によるとキメラ遺伝子は主としてAML1の機能を抑制する機能を持つことが判明している。我々は急性骨髄性白血病の患者のAML1遺伝子に点突然変異を見出し、AML1の一方の遺伝子座の機能消失で白血病になり易い状態を作り、両方の遺伝子座の機能消失で白血病を誘発する可能性を強く示唆するデータを得た。これらの結果より我々は「AML1のloss-of-function変異は白血病原性を示す」という仮説に到達した。その後アメリカのグループよりAML1の一方の遺伝子座に家族性に変異を持つ人達が高頻度で急性骨髄性白血病を発症する新しい病気FPD/AML1が発表され、我々の仮説が強い支持を得た。これらの経緯よりAML1^<+/->マウスは白血病を誘発しやすいことが考えられる。我々はこのヘテロ変異体の9.5日胚より造血能を持つ血管内皮細胞を集め、in vitroで培養することによりAML1^<+/->では骨髄球の分化がAML1^<+/+>より遅延していることを観察し、上記仮説を支持するデータを得た。またAML1^<+/->より得た造血能を持つ血管内皮細胞の増殖分化はAML1^<+/+>のものに比し顆粒球コロニー促進因子、G-CSFに極めて強く依存することも観察された。この現象も骨髄性自血病の誘発と強く関連するものと考えられ解析を続けている。

Research Products
(16 results)

All Other

All Publications (16 results)

[Publications] Ito, Y.: "Molecular basis of tissue-specific gene expression mediated by the Runt domain transcription factor PEBP2/CBF"GENES TO CELLS. 90. 1270-1272 (1999)
[Publications] Wener, M. H.: "Runt-domain take the lead in hematopoiesis and osteogenesis"Nature Medicine. 5. 1356-1357 (1999)
[Publications] Zhang, Y. -W.: "PEBP2αA/CBFA1 mutations in Japanese Cleidocranial Dysplasia patients"Gene. (in press).
[Publications] 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)
[Publications] Goger, M.: "Molecular insights into PEBP2/CBFβ-SMMHC associated acute leukemia revealed from the structure of PEBP2/CBFβ"Nature Struct. Biol.. 6. 620-623 (1999)
[Publications] Nagata, T.: "Immunoglobulin motif DNA recognition and heterodimerization for the PEBP2/CBF Runt-domain"Nature struct. Biol.. 6. 615-619 (1999)
[Publications] 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)
[Publications] Kim. W. -Y.: "Mutual activation of Ets-1 and AML1 DNA binding by direct interaction of their autoinhibitory domains"EMBO J.. 18. 1609-1620 (1999)
[Publications] 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)
[Publications] 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)
[Publications] 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)
[Publications] 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)
[Publications] 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)
[Publications] Hwang, E. S.: "Regulation of c-fos gene transcription and myeloid cell differentiation by acute myeloid leukemia 1 and acute myeloid leukemia-MTG8, a chimeric leukemogenic derivative of acute myeloid leukemia 1"FEBS Letters. 446. 86-90 (1999)
[Publications] Bae, S. -C.: "Regulation mechanisms for the heterodimeric transcription factor, PEBP2/CBF"Histl. Histopathol. 14. 1213-1221 (1999)
[Publications] Mukoyama, Y.: "The AML1 transcription factor functions to develop and maintain hematogenic precursor cells in the embryonic aorta-gonad mesonephros region"Development Biol.. (in press).

1999 Fiscal Year Annual Research Report

転写因子PEBP2の構造異常による白血病発症の機序

Principal Investigator

伊藤 嘉明 京都大学, ウイルス研究所, 教授 (80004612)

Research Products

[Publications] Ito, Y.: "Molecular basis of tissue-specific gene expression mediated by the Runt domain transcription factor PEBP2/CBF"GENES TO CELLS. 90. 1270-1272 (1999)

[Publications] Wener, M. H.: "Runt-domain take the lead in hematopoiesis and osteogenesis"Nature Medicine. 5. 1356-1357 (1999)

[Publications] Zhang, Y. -W.: "PEBP2αA/CBFA1 mutations in Japanese Cleidocranial Dysplasia patients"Gene. (in press).

[Publications] 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)

[Publications] Goger, M.: "Molecular insights into PEBP2/CBFβ-SMMHC associated acute leukemia revealed from the structure of PEBP2/CBFβ"Nature Struct. Biol.. 6. 620-623 (1999)

[Publications] Nagata, T.: "Immunoglobulin motif DNA recognition and heterodimerization for the PEBP2/CBF Runt-domain"Nature struct. Biol.. 6. 615-619 (1999)

[Publications] 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)

[Publications] Kim. W. -Y.: "Mutual activation of Ets-1 and AML1 DNA binding by direct interaction of their autoinhibitory domains"EMBO J.. 18. 1609-1620 (1999)

[Publications] 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)

[Publications] 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)

[Publications] 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)

[Publications] 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)

[Publications] 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)

[Publications] Hwang, E. S.: "Regulation of c-fos gene transcription and myeloid cell differentiation by acute myeloid leukemia 1 and acute myeloid leukemia-MTG8, a chimeric leukemogenic derivative of acute myeloid leukemia 1"FEBS Letters. 446. 86-90 (1999)

[Publications] Bae, S. -C.: "Regulation mechanisms for the heterodimeric transcription factor, PEBP2/CBF"Histl. Histopathol. 14. 1213-1221 (1999)

[Publications] Mukoyama, Y.: "The AML1 transcription factor functions to develop and maintain hematogenic precursor cells in the embryonic aorta-gonad mesonephros region"Development Biol.. (in press).

伊藤嘉明京都大学, ウイルス研究所, 教授 (80004612)