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2000 Fiscal Year Final Research Report Summary

Mechanisms of apoptosis and differentiation induced by arsenic trioxide in leukemic cells and its clinical application

Research Project

Project/Area Number 11671015
Research Category

Grant-in-Aid for Scientific Research (C)

Allocation TypeSingle-year Grants
Section一般
Research Field Hematology
Research InstitutionKeio University

Principal Investigator

KIZAKI Masahiro  Keio Univ.School of Medicine, Dept.Internal Medicine, Assistant Profess, 医学部, 講師 (20161432)

Co-Investigator(Kenkyū-buntansha) IKEDA Yasuo  Keio Univ.School of Medicine, Dept.Internal Medicine, Professor, 医学部, 教授 (00110883)
FUKUCHI Yumi  Keio Univ.School of Medicine, Dept.Internal Medicine, Research Associate, 医学部, 助手 (40250237)
Project Period (FY) 1999 – 2000
Keywordsarsenic trioxide / leukemia / apoptosis / differentiation / retinoic acid / GM-CSF / SCID mice / PML / RARα
Research Abstract

Arsenic trioxide effectively induces clinical remission via apoptosis in relapsed acute promyelocytic leukemia (APL). However, its molecular mechniams od inducing apoptosis is still unclear. In addition, this new anti-leukemic drug is considered to be a poison, its possible adverse effects are a highly important issue related to its clinical use. Arsenic trioxide can induce apoptosis of both retinoic acid-sensitive NB4 and-resistant UF-1 cells with down-regulation of Bcl-2 and up-regulation of Bax proteins, respectively. Also, arsenic trioxide degrades APL-specific PML/RARα fusion protein. Interestingly, a combination of arsenic trioxide and GM-CSF induces differentiation, but not apoptosis of APL cells. GM-CSF was found to be associated with increased tyrosine phosphorylation of Jak2 kinase in both NB4 and UF-1 cells. A specific inhibitor of Jak2, AG490, completely blocked the ability of GM-CSF to prevent apoptosis and induce differentiation of arsenic trioxide-treated APL cells, suggesting that Jak/STAT pathway is dritical for the anti-apoptotic activity of GM-CSF in APL cells treated with both agents. These results are also observed in vivo by using human GM-CSF-producing transgenic SCID mice model. In conclusion, a combination of arsenic trioxide and GM-CSF appears to be a novel differentiation-inducing therapy in patients with APL.Further molecular studies to determine the target molecules of arsenic trioxide will be needed.

  • Research Products

    (30 results)

All Other

All Publications (30 results)

  • [Publications] 木崎昌弘: "レチノイン酸受容体と白血病"医学のあゆみ. 190. 335-340 (1999)

    • Description
      「研究成果報告書概要(和文)」より
  • [Publications] 木崎昌弘: "急性前骨髄球性白血病の分化誘導療法-レチノイン酸とヒ素"内科. 84. 518-520 (1999)

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      「研究成果報告書概要(和文)」より
  • [Publications] 木崎昌弘: "白血病の分化誘導療法の新しい展開"臨床血液. 41. 173-176 (2000)

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      「研究成果報告書概要(和文)」より
  • [Publications] 福地由美 他: "APLのモデルマウス"分子細胞治療. 1. 401-406 (2000)

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      「研究成果報告書概要(和文)」より
  • [Publications] 木崎昌弘: "白血病の分化誘導療法"日本医師会雑誌. 124. S308-S310 (2000)

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      「研究成果報告書概要(和文)」より
  • [Publications] Muto A, et al: "1, 25-di hydrohyvitamin D_3 induces differentiation of retinoic acid-resistant APL cell line (UF-1) associated with expression of P21 and P2F"Blood. 93. 2225-2233 (1999)

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      「研究成果報告書概要(和文)」より
  • [Publications] Kinje K, et al: "Serum thrombopoietin and erythropoietin levels in patients with acute promyelocytic leukaemia during all-trans retinoic acid treatment."Br.J.Haematol.. 105. 382-387 (1999)

    • Description
      「研究成果報告書概要(和文)」より
  • [Publications] Fukuchi Y. et al: "Human acute myeloblastic leukemia ascites model using the human GM-CSF and IL-3-releasing transgenic SCID mice"Ann.Hematol.. 78. 223-231 (1999)

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      「研究成果報告書概要(和文)」より
  • [Publications] Kizaki M. et al: "A novel retinoic acid-resistant acute promyelocytic leukemia model in vitro and in vivo"Int.J.Mol.Med.. 4. 359-364 (1999)

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      「研究成果報告書概要(和文)」より
  • [Publications] Matsushita H. et al: "Induction of apoptosis in myeloid leukemic cells py ribozymes targeted against AML1/MIG8."Br.J.Cancer. 79. 1325-1331 (1999)

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  • [Publications] Kinjo K, et al: "Arsenic Trioxide(As_2O_3)-induced apoptosis and differentiation in retinoic acid-resistant acute promyelocytic leukemia model in hGM-CSF-producing transgenic SCID mice."Leukemia. 14. 431-438 (2000)

    • Description
      「研究成果報告書概要(和文)」より
  • [Publications] Yamato K, et al: "Dissociation of bone morphogenetic protein-mediated growth arrest and apoptosis of mouse B cells by HPV-16 E6/E7"Exp.cell Res.. 257. 198-205 (2000)

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      「研究成果報告書概要(和文)」より
  • [Publications] Kawamura C. et al.: "Bone morphogenetic protein (BMP)-2 induces apoptosis in human myeloma cells with modulation of STAT3"Blood. 96. 2005-2011 (2000)

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      「研究成果報告書概要(和文)」より
  • [Publications] Fukuchi Y., et al: "Mcl-1, an early-induction molecule, modulates action A-induced apoptosis and differentiation of CMC cells"Oncogene. (in press).

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      「研究成果報告書概要(和文)」より
  • [Publications] 木崎昌弘: "Annual Review 血液1999"高久史麿,溝口秀昭,小宮山淳,坂田洋一,金倉讓(編). 257 (1999)

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      「研究成果報告書概要(和文)」より
  • [Publications] Kizaki M.: "Molecular targets for hematological malignancies and cancer"Niho Y(ed). 198 (2000)

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      「研究成果報告書概要(和文)」より
  • [Publications] Kizaki M: "Ribotyme Technology and application"Krupp G and Gauer R(eds). 514 (2000)

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      「研究成果報告書概要(和文)」より
  • [Publications] Kizuki M: "Cell therapy Keio University Symposia for Life Science and Medicine"Ikida Y, Hata J, Koyasu S, Kawakomi Y, Hottori Y (eds). 240 (2000)

    • Description
      「研究成果報告書概要(和文)」より
  • [Publications] Muto A, Kizaki M, Yamato K, Kawai Y, Matsushita-Kamata M, Ueno H, Ohguchi M, Nishihara T, Koeffler HP and Ikeda Y: "1,25-dihydroxyvitamin D3 induces differentiation of retinoic acid-resistant APL cell line (UF-1) associated with expression of p21^<WAF1/CIP1> and p27^<KIP1>"Blood. 93 (7). 2225-2233 (1999)

    • Description
      「研究成果報告書概要(欧文)」より
  • [Publications] Kinjo K, Kizaki M, Takayama N, Michikawa N, Oda A, Okamoto S, Tahara H, Kato T, Miyazaki H and Ikeda Y: "Serum thrombopoietin and erythropoietin levels in patients with acute promyelocytic leukaemia during all-trans retinoic acid treatment."British Journal of Haematology. 105 (2). 382-387 (1999)

    • Description
      「研究成果報告書概要(欧文)」より
  • [Publications] Fukuchi Y, Miyakawa Y, Kizaki M, Umezawa A, Shimamura K, Kobayashi K, Kuramochi T, Hata J, Ikeda Y, Tamaoki K, Nomura T, Ueyama Y and Ito M: "Human acute myeloblastic leukemia-ascites model using the human GM-CSF-and IL-3-releasing transgenic SCID mice."Annals of Hematology. 78 (5). 223-231 (1999)

    • Description
      「研究成果報告書概要(欧文)」より
  • [Publications] Kizaki M, Fukuchi Y and Ikeda Y: "A novel retinoic acid-resistant acute promyelocytic leukemia model in vitro and in vivo."International Journal of Molecular Medicine. 4 (4). 359-364 (1999)

    • Description
      「研究成果報告書概要(欧文)」より
  • [Publications] Matsushita H, Kizaki M, Kobayashi H and Ikeda Y: "Induction of apoptosis in myeloid leukemic cells by ribozymes targeted against AML1/MTG8."British Journal of Cancer. 79 (9/10). 1325-1331 (1999)

    • Description
      「研究成果報告書概要(欧文)」より
  • [Publications] Kinjo K, Kizaki M, Muto A, Fukuchi Y, Umezawa A, Yamato K, Nishihara T, Hata J, Ito M, Ueyama Y and Ikeda Y: "Arsenic trioxide (As2O3)-induced apoptosis and differentiation in retinoic acid-resistant acute promyelocytic leukemia model in hGM-CSF-producing transgenic SCID mice."Leukemia. 14 (3). 431-438 (2000)

    • Description
      「研究成果報告書概要(欧文)」より
  • [Publications] Yamato K, Hashimoto S, Okahashi N, Ishisaki A, Nonaka K, Koseki T, Kizaki M, Ikeda Y and Nishihara T: "Dissociation of bone morphogenetic protein-mediated growth arrest and apoptosis of mouse B cells by HPV-16 E6/E7."Experimental Cell Research. 257 (1). 198-205 (2000)

    • Description
      「研究成果報告書概要(欧文)」より
  • [Publications] Kawamura C, Kizaki M, Yamato K, Uchida H, Fukuchi Y, Hattori Y, Koseki T, Nishihara T and Ikeda Y: "Bone morphogenetic protein (BMP)-2 induces apoptosis in human myeloma cells with modulation of STAT3."Blood. 96 (6). 2005-2011 (2000)

    • Description
      「研究成果報告書概要(欧文)」より
  • [Publications] Fukuchi Y, Kizaki M, Yamato K, Kawamura C, Umezawa A, Hata J, Nishihara T and Ikeda Y: "Mcl-1, an early-induction molecule, modulates activin A-induced apoptosis and differentiation of CML cells."Oncogene. (in press).

    • Description
      「研究成果報告書概要(欧文)」より
  • [Publications] Kizaki M: "Molecular mechanisms of retinoid-resistance in acute promyelocytic leukemia (APL) and recent advances of differentiation-inducing therapy for leukemia."Molecular targets for hematological malignancies and cancer.. Y.Niho (ed) Kyushu University Press, Fukuoka, Japan. 75-84 (2000)

    • Description
      「研究成果報告書概要(欧文)」より
  • [Publications] Kizaki M, Matsushita H and Ikeda Y: "Therapeutic applications of ribozymes for leukemic cells with t(8 ; 21) and the mechanism of their anti-leukemic effect."Ribozyme technology and applications. G.Krupp and R.Gauer (eds) Bio Techniques Books, Eaton Publishing, Natick, MA. 483-500 (2000)

    • Description
      「研究成果報告書概要(欧文)」より
  • [Publications] Kizaki M: "A novel acute promyelocytic leukemia model : from cell to murine system. In : Cell therapy."Keio University Symposia for Life Science and Medicine. Y.Ikeda, J.Hata, S.Koyasu, Y.Kawakami and Y.Hattori (eds) Springer-Verlag Tokyo, Tokyo, Japan. Vol.5. 133-142 (2000)

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      「研究成果報告書概要(欧文)」より

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Published: 2002-03-26  

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