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Research on the mechanism of resistance to retinoic aid in acute promyelocytic leukemia

Research Project

Project/Area Number 10670702
Research Category

Grant-in-Aid for Scientific Research (C)

Allocation TypeSingle-year Grants
Section一般
Research Field Pediatrics
Research InstitutionTOHOKU UNIVERSITY

Principal Investigator

IMAIZUMI Masue  School of Medicine, Tohoku University, Associate Professor, 大学院・医学系研究科, 助教授 (40191895)

Co-Investigator(Kenkyū-buntansha) SUZUKI Hosiro  School of Medicine, Tohoku University, Research Associate, 医学部・附属病院, 助手 (00292334)
IDE Hiroyuki  School of Science, Tohoku University, Professor, 大学院・理学研究科, 教授 (70022704)
Project Period (FY) 1998 – 1999
Project Status Completed (Fiscal Year 1999)
Budget Amount *help
¥3,500,000 (Direct Cost: ¥3,500,000)
Fiscal Year 1999: ¥1,300,000 (Direct Cost: ¥1,300,000)
Fiscal Year 1998: ¥2,200,000 (Direct Cost: ¥2,200,000)
KeywordsAcute promyelocytic / retinoic aid / ATRA resistance / PML / RARα / acquired mutatien / APL / ATRA耐性機序 / RARα変異
Research Abstract

The binding of all-trans retinoic acid (ATRA) to the ligand-binding region in the E-domain of retinoic acid receptor-alpha modifies the transcriptional activity of RARalpha protein. ATRA probably induces differentiation of acute promyelocytic leukemia (APL) cells by binding to the E-domain of the RARalpha portion (RARalpha/E-domain) of PML/RARalpha chimeric protein. Therefore, molecular alteration in the RARalpha/E-domain of the chimeric gene is one mechanism by which patients with APL may acquire resistance to ATRA therapy. In this study reverse transcription-polymerase chain reaction and single-strand conformation polymorphism, DNA segments amplified from the RARalpha/E-domain in fresh APL cells of 23 APL patients (8 males and 15 females from 4 to 76 years of age) were screened for mutations. OF those patients, 3 patients (1 with de novo and 2 with relapse) had clinical resistance to ATRA therapy. We found mutations in the RARalpha/E-domain of PML/RARalpha chimeric gene exclusively in the 2 patients who exhibited ATRA-resistance at relapse, whereas the mutations were not detected at their initial onset. Interestingly, these patients received a prolonged or intermittent administration of ATRA before relapse with ATRA-resistance. The mutations lead to the change of amino acid in the ligand-binding region of RARalpha/E-domain, Arg272Gln, or Met297Leu according to the amino acid sequence of RARalpha, respectively. Further study that the in vitro ligand-dependent transcriptional activity of the mutant PML/RARalpha protein was significantly decreased as compared with that of wild-type PML/RARalpha. These findings suggest that mutations in the RARalpha/E-domain of the PML/RARalpha chimeric gene may confer clinical resistance to ATRA therapy in patients with APL.

Report

(3 results)
  • 1999 Annual Research Report   Final Research Report Summary
  • 1998 Annual Research Report
  • Research Products

    (24 results)

All Other

All Publications (24 results)

  • [Publications] Fuji K,Matsubara Y,Akanuma J,Kure S,Suzuki Y.Imaizumi M,et al.: "Mutation detected by TaqMan-allele specific amplification : its application to the molecular diagnosis of glycogen storage disease type Ia and medium-chain acyl-CoA dehydogenase deficiency"Hum Mutatuion (in press). (2000)

    • Description
      「研究成果報告書概要(和文)」より
    • Related Report
      1999 Final Research Report Summary
  • [Publications] Yoshinari M,Imaizumi M,Suzuki H,Chikaoka S,Iinuma K,et al.: "G-CSF induces apoptosis of a human promyelocytic leukemia cell line, UF-1 : Possible involvement of STAT3 activation and alrered BAX expression"Tohoku J Exp Med. 189. 71-82 (1999)

    • Description
      「研究成果報告書概要(和文)」より
    • Related Report
      1999 Final Research Report Summary
  • [Publications] Kimura T,Akaba K,Ikegami T,Katsuura M,Imaizumi M,et al.: "Intermittent Jaundice In patients with acute leukemia : a common mutation of the bilirubin uridine diphosphate glucuronosyltransferase gene among Asians"J Inheri Metabol Dis. 22. 743-753 (1999)

    • Description
      「研究成果報告書概要(和文)」より
    • Related Report
      1999 Final Research Report Summary
  • [Publications] Sato A,Imaizumi M,Saisho T,Yosinari M,Suzuki H,Hayashi Y and Iinuma K.: "Detection of apoptosis in acute promyelocytic leukemia in vivo during defferentiation-induction therapy with all-trans retinoic acid in combination of chemotherapeutic agents"Leukemia Res. 23. 827-832 (1999)

    • Description
      「研究成果報告書概要(和文)」より
    • Related Report
      1999 Final Research Report Summary
  • [Publications] Nishimura S,Kobayashi M,Ueda K,Okamura J,Imaizumi M,et al.: "Treatment of infant acute Iymphoblastic leukemia In Japan. Childhood Leukemia Study Group of the Ministry of Health and Welfare"Int J Hematol. 69. 244-252 (1999)

    • Description
      「研究成果報告書概要(和文)」より
    • Related Report
      1999 Final Research Report Summary
  • [Publications] Kawasaki S,Oshitani H,Suzuki H,Arakawa M,Imaizumi M,et al.: "PCR-RFLP analysis of cytomegalovirus infections associated with bone marrow transplantation in Japanese children"Microbiol Immunol. 43. 359-364 (1999)

    • Description
      「研究成果報告書概要(和文)」より
    • Related Report
      1999 Final Research Report Summary
  • [Publications] Fuji K, Matsubara Y, Akanuma J, Kure S, Suzuki Y, Imaizumi M, et al.: "Mutation detected by TaqMan-allele specific amplification : its application to the molecular diagnosis of glycogen storage disease type Ia and medium-chain acyl-CoA dehydogenase deficiency"Hum Mutation. (in press). (2000)

    • Description
      「研究成果報告書概要(欧文)」より
    • Related Report
      1999 Final Research Report Summary
  • [Publications] Yoshinari M, Imaizumi M, Suzuki H, Chikaoka S, Iinuma K, et al.: "G-CSF induces apoptosis of a human promyelocytic leukemia cell line, UF-1 : Possible involvement of STAT3 activation and alrered BAX expression"Tohoku J Exp Med. 189. 71-82 (1999)

    • Description
      「研究成果報告書概要(欧文)」より
    • Related Report
      1999 Final Research Report Summary
  • [Publications] Kimura T, Akaba K, Ikegami T, Katsuura M, Imaizumi M, et al.: "Intermittent jaundice in patients with acute leukemie : a common mutation of the bilirubin uridine diphosphate glucuronosyltransferase gane among Asians"J Inheri Metabol Dis. 22. 743-753 (1999)

    • Description
      「研究成果報告書概要(欧文)」より
    • Related Report
      1999 Final Research Report Summary
  • [Publications] Sato A, Imaizumi M, Sisho T, Yosinari M, Suzuki H, Hayashi Y and Iinuma K: "Detection of apoptosis in acute promyelocytic leukemia in vivo during differentiation-induction therapy with all-trans retinoic acid in combination of chemotherapeutic agents"Leukemia Res. 23. 827-832 (1999)

    • Description
      「研究成果報告書概要(欧文)」より
    • Related Report
      1999 Final Research Report Summary
  • [Publications] Nishimura S, Kobayashi M, Ueda K, Okamura J, Imaizumi M, et al.: "Treatment of infant acute Iymphoblastic leukemia in Japan. Childhood Leukemia Study Group of the Ministry of Health and Welfare"Int J Hematol. 69. 244-252 (1999)

    • Description
      「研究成果報告書概要(欧文)」より
    • Related Report
      1999 Final Research Report Summary
  • [Publications] Kawasaki S, Oshitani H, Suzuki H, Arakawa M, Imaizumi M, et al.: "PCR-RFLP analysis of cytomegalovirus infection associated with bone marrow transplantation in Japanese children"Microbiol Immunol. 43. 359-364 (1999)

    • Description
      「研究成果報告書概要(欧文)」より
    • Related Report
      1999 Final Research Report Summary
  • [Publications] Fuji K.,Matsubara Y.,Akanuma J.,Takahashi K.,Kure S.,Suzuki Y.,Imaizumi M.,Iinuma K.,Sakamoto O.,Rinnaldo P.and Narisawa K.: "Mutation detected by TaqMan-allele specific amplification : its application to the molecular diagnosis of glycogen storage disease type Ia and medium-chain acyl-CoA dehydogenase deficiency"Hum Mutation. (in press).

    • Related Report
      1999 Annual Research Report
  • [Publications] Yoshinari M.,Imaizumi M.,Sato A, Saito T.,Suzuki H.,Chikaoka S.,Kizaki M.,Funato T.,Hayashi Y.and Iinuma K.: "G-CSF induces apoptosis of a human promyelocytic leukemia cell lime, UF-1: Possible involvement of STAT3 activation and alrered BAX expression"Tohoku J Exp Med. 189. 71-82 (1999)

    • Related Report
      1999 Annual Research Report
  • [Publications] Kimura T.,Akaba K.,Ikegami T.,Akiba K.,Kanazawa C.,Katsuura M.,Shimizu Y.,Imaizumi M., Lin C.and Hayasaka K.: "Intermittent jaundice in patients with acute leukemia : a common mutation of the bilirubin uridine diphosphate glucuronosyltransferase gene among Asians"J Inheri Metabol Dis. 22. 743-753 (1999)

    • Related Report
      1999 Annual Research Report
  • [Publications] Sato A.,Imaizumi M.,Saisho T., Saito T.,Yoshinari M.,Suzuki H.,Hayashi Y.and Iinuma M.: "Detection of apoptosis in acute promyelocytic leukemia in vivo during differentiation-induction therapy with all-trans retinoic acid in combination of chemotherapeutic agents"Leukemia Res. 23. 827-832 (1999)

    • Related Report
      1999 Annual Research Report
  • [Publications] Nishimura S.,Kobayasi M.,Ueda K.,Ishii E.,Okamura J.,Kawa-Ha K.,Akiyama Y.,Imashuku S.,Horibe K.,Matsuyama T.,Imaizum M.,Tsukimoto I.,Nagao T.: "Treatmant of infant acute lymphoblastic lenkemia in Japan. Childhood Leukemia Study Group of the Ministry of Health and Welfare"Int Hematol. 69. 244-252 (1999)

    • Related Report
      1999 Annual Research Report
  • [Publications] Kawaski S.,Oshitani H.,Suzuki H.,Arakawa M.,Mizuta K.,Imaizumi M.,Tsuchiya S.and Konno T.: "PCR-RFLP analysis of cytomegalovirus infections associated with bone marrow transplantion in Japanese children"Microbiol Immunol. 43. 359-364 (1999)

    • Related Report
      1999 Annual Research Report
  • [Publications] Imaizumi M et al.: "Mutations in tha E-domain of RARa portion of PML/RARa chimeric gene may confer clinical resistance to all-trans retinoic acid in asute promyclocytic leukemia." Blood. 92. 374-382 (1998)

    • Related Report
      1998 Annual Research Report
  • [Publications] Yoshinari M.Imaizumi M et al.: "Peripheral blood stem cell transplantation for hepatoblastoma with microscopic residue : A therapeutic approach for incompletely resected tumor" Tohoku J Exp.Med. 185. 247-254 (1998)

    • Related Report
      1998 Annual Research Report
  • [Publications] Imaizumi M et al.: "Primary cutancous T-cell lymphoma involving the cheek : An infant case with a unique clinicopathologic feature." Leuk Lymphoma. 31. 225-229 (1998)

    • Related Report
      1998 Annual Research Report
  • [Publications] Yoshinari M.Imaizumi M et al.: "Establishment of a novel pre-B acute lymphoblastic leukemia cell line, TS-2, with t (1;19) chromosomal translocation not involving E2A gene." Cancer Genet Cytogenet. 101. 95-102 (1998)

    • Related Report
      1998 Annual Research Report
  • [Publications] Kawasaki S.Imaizumi M et al.: "Cytomegalovirus monitoring by culture swabs from Japanese children undergoing autologaous bone marrow or peripheral blood progenitor cell or allogeneic bone marrow transplantation." J Infect Dis. 177. 519 (1998)

    • Related Report
      1998 Annual Research Report
  • [Publications] Sato A.Imaizumi M et al.: "Improved survival of children with advanced solid tumors treated with autologous peripheral blood stem cell transplantation in complete remission." Tohoku J Exp Med. 187(in press). (1999)

    • Related Report
      1998 Annual Research Report

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Published: 1998-04-01   Modified: 2016-04-21  

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