Mechanisms of leukemogenesis caused by alterations of the structure of transcription factor PEBP2

• Project/Area Number: 09253220
• Research Category: Grant-in-Aid for Scientific Research on Priority Areas
• Allocation Type: Single-year Grants
• Research Institution: Institute for Virus Research, Kyoto University
• Principal Investigator: ITO Yoshiaki Institute for Virus Research, Kyoto University : Professor, ウイルス研究所, 教授 (80004612)
• Co-Investigator(Kenkyū-buntansha): MARUYAMA Mitsuo Institute for Virus Research, Kyoto University : Instructor, ウイルス研究所, 助手 (00212225) ; KANNO Tomohiko Institute for Virus Research, Kyoto University : Instructor, ウイルス研究所, 助手 (10273525)
• Project Period (FY): 1994 – 1999
• Project Status: Completed (Fiscal Year 2000)
• Budget Amount: ¥75,000,000 (Direct Cost: ¥75,000,000); Fiscal Year 1999: ¥30,000,000 (Direct Cost: ¥30,000,000); Fiscal Year 1998: ¥30,000,000 (Direct Cost: ¥30,000,000); Fiscal Year 1997: ¥15,000,000 (Direct Cost: ¥15,000,000)
• Keywords: RUNX1 / RUNX2 / RUNX3 / AML1 / PEBP2 / FPD-AML / TGF-β / BMP / 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

Research Abstract

Transcription factor PEBP2 is composed of α and β subunits. There are three genes encoding the α subunit, RUNX1/AML1, RUNX2/CBFA1, RUNX3/PEBP2αC.We found that RUNX1 is required for generation of hematopoietic stem cells from endothelial cells. RUNX1 is the most frequent target of chromosome translocations associated with acute leukemia but we found sporadic loss-of-function point mutations without involving chimeric proteins. Later, familial cases of point mutations were reported which are called Familial Patelet Disorder with Predisposition to Acute Myeloid Leukemia (FPD-AML). Mice carrying heterozygously disrupted RUNX1 gene were found to be a good mouse model for FPD-AML.Haploinsufficiency of RUNX1 is being proved to be leukemogenic.
RUNX2 is essential for maturation of chondrocytes and osteoblasts. Haploinsufficiency of RUNX2 causes cleidocranial dysplasia (CCD). We found that RUNX2 is one of the major target of TGF-β/BMP signaling and mutations of RUNX2 impaired the BMP pathway to cause CCD.
We found that RUNX3 was expressed in epithelial cells of gastrointestinal tractand that the disruption of the gene caused hyperplasia of epithelial layer of glandular stomach. Possible involvement of RUNX3 in gastric cancer is being studied.

Research Products

• [Publications] 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)
  • Description: 「研究成果報告書概要(和文)」より
• [Publications] 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)
  • Description: 「研究成果報告書概要(和文)」より
• [Publications] 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)
  • Description: 「研究成果報告書概要(和文)」より
• [Publications] 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)
  • Description: 「研究成果報告書概要(和文)」より
• [Publications] Nagata et al.: "Immunoglobulin motif DNA recognition and heterodimerization for the PEBP2/CBF Runt-domain."Nature Struct.Biol.. 6. 615-619 (1999)
  • Description: 「研究成果報告書概要(和文)」より
• [Publications] Werner et al.: "Runt-domain take the lead in hematopoiesis and osteogenesis."Nature Medicine. 5. 1356-1357 (1999)
  • Description: 「研究成果報告書概要(和文)」より
• [Publications] 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)
  • Description: 「研究成果報告書概要(欧文)」より
• [Publications] 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)
  • Description: 「研究成果報告書概要(欧文)」より
• [Publications] 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)
  • Description: 「研究成果報告書概要(欧文)」より
• [Publications] 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)
  • Description: 「研究成果報告書概要(欧文)」より
• [Publications] 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)
  • Description: 「研究成果報告書概要(欧文)」より
• [Publications] Werner et al.: "Runt-domain take the lead in hematopoiesis and osteogenesis."Nature Medicine. 5. 1356-1357 (1999)
  • Description: 「研究成果報告書概要(欧文)」より
• [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).
• [Publications] Yagi,R.: "A WW domain-containing Yes-associated protein(YAP)is a novel transcriptional co-activator." EMBO J.(in press).
• [Publications] Kohzaki,H.: "Block of granulocytic differentiation of 32Dc13 cells by AML1/ETO(MTG8)but not by highly expressed Bcl-2." Oncogne. (in press).
• [Publications] Li,J.: "Smad2 overexpression enhances Smad4 gene expression and suppresses CBFA1 gene expression on osteoblastic osteosarcoma ROSI7/2.8 cells." J.Biological Chem.273. 31009-31015 (1998)
• [Publications] Okada,H.: "AML1(-/-embryos so not express certain hematopoiesis-related gene transcripts including those of the PUI gene." Oncogene. 17. 2287-2293 (1998)
• [Publications] Kogan,S.: "The PEBP2βMYH11 fusion created by Inv(16)(p13;q22)in myeloid leukemia impairs neutrophil maturation and contributes to granulocvtic dysplasia." Proc.Natl.Acad.Sci.USA. 95. 11863-11868 (1998)
• [Publications] Kim,W.-Y.: "Mutual activation of Ets-1 and AML1 DNA binding by direct interaction of their autoinhibitory domains." EMBOJ.18. 1609-1620 (1999)
• [Publications] Osato,M.: "Biallelic and heterozygous point mutations in the Runt domain of the AML1/PEBP2αB gene associated with myeloblastic leukemias." Blood. (in press).
• [Publications] Tanaka,Y.: "The chimeric protein,PEBP2β/CBFβ-S,SMMHC,disorganizes cytoplasmic stress fibers and inhibits transcriptional activation." Oncogene. 17. 699-708 (1998)
• [Publications] 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)
• [Publications] Chen,L.-F.: "The capacity of PEBP2αB(AML1/Cbfa2)to stimulate polyomavirus DNA replication is related to its affinity for the nuclear matrix." Mol.Cell.Biol.18. 4165-4176 (1998)
• [Publications] 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)
• [Publications] 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)
• [Publications] Sato,M.: "Transcriptional regulation of osteopontin gene in vivo by PEBP2αA/CBF and ETS1 in the skeletal tissues." Oncogene. 17. 1517-1525 (1998)
• [Publications] 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)
• [Publications] 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)
• [Publications] 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)
• [Publications] 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)
• [Publications] Ito Y.: "The runt protein and its companion PEBP2 : A close link between this transcription factor and AML." Leukemia. Suppl 3. 279-280 (1997)
• [Publications] 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)
• [Publications] Zhang Y-W.: "A novel transcript encoding an N-terminally truncated AML21/PEBP2αB protein interferes with transactiyation and blocks the granulocytic differentiation of 32CDc13 myeloid cells." Mo1.Cell.Biol.17. 4133-4145 (1997)