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Analysis of tumor suppressor gene in childhood leukemia and its application to clinical aspects

Research Project

Project/Area Number 08670857
Research Category

Grant-in-Aid for Scientific Research (C)

Allocation TypeSingle-year Grants
Section一般
Research Field Pediatrics
Research InstitutionUniversity of Tokyo

Principal Investigator

SIBUYA Kazuhiko (1997)  Univ.of Tokyo, Faculty of Medicine, Assistant Professor, 医学部・附属病院, 助手 (80206151)

小林 茂俊 (1996)  東京大学, 医学部・附属病院, 助手 (70260487)

Co-Investigator(Kenkyū-buntansha) ISODA Takayoshi  Univ.of Tokyo, Faculty of Medicine, Assistant Professor, 医学部・附属病院, 助手 (80272574)
KOBAYASHI Miyuki  Univ.of Tokyo, Faculty of Medicine, Assistant Professor, 医学部・附属病院, 助手 (60205391)
HAYASHI Yasuhide  Univ.of Tokyo, Faculty of Medicine, Associate Professor, 医学部・附属病院, 講師 (30238133)
YANAGISAWA Masayoshi  Univ.of Tokyo, Faculty of Medicine, Professor, 医学部・附属病院, 教授 (90049031)
渋谷 和彦  東京大学, 医学部・附属病院, 助手 (80206151)
Project Period (FY) 1996 – 1997
Project Status Completed (Fiscal Year 1997)
Budget Amount *help
¥2,600,000 (Direct Cost: ¥2,600,000)
Fiscal Year 1997: ¥1,400,000 (Direct Cost: ¥1,400,000)
Fiscal Year 1996: ¥1,200,000 (Direct Cost: ¥1,200,000)
Keywordsacute lymphoblastic leulemia / p16 gene / p15 gene / p53 gene / RAS gene / tumor suppressor gene / methylation / 急性リンパ性白血癌 / P16遺伝子 / P15遺伝子 / FHIT遺伝子 / FLT3遺伝子 / DCC遺伝子 / サザン解析 / P53遺伝子
Research Abstract

Homozygous deletions (HD) of p16 and p15 genes and mutations of p16, RAS and p53 genes ere examined in B precursor acute lymphoblastic leukemia (ALL). Of 10 cell lines without t(1 ; 19), HD was found in 8 (80%), and a rearrangement of p16 in one cell line (10%). In contrast, only one (20%) of the 5 cell lines with t(1 ; 19) showed HD or rearrangement of p16/p 15 gene. Thirteen of 60 (22%) primary samples demonstrated HD of the p16 gene. No case with t(l ; 19) showed HD of the p16 gene (0/13), while cases without t(1 ; 19) showed considerable incidence of HD of the p16 gene (13/47,28%). Nine of 45 (20%) samples at diagnosis and four of 22 (18%) samples at relapse showed HD of p16. The similarity of the rate in these two groups raises the question of the role of p16 gene in progression of B precursor ALL.Remarkably, mutations were found in 3 of the primary cases (5%). As for leukemia with MLL rearrangement (MLL+), HD of the p16 and p15 genes was found in 5 (11%) of 19 acute myeloid leuke … More mias (AMLs), Patients with HD of pl6 and p15 genes showed higher average leukocyte counts and lower survival rates than those with normal p16 and p15 genes (14.3 vs 30.7%, not significant). PCR-single strand conformation polymorphism (SSCP) showed no mutationin in the 32 patients tested. Our results suggest that alterations of 16 and p15 genes are involved in a subset of acute leukemias with MLL+ not only of lymphoid but also of myeloid phenotype. Mutations of the p53 gene were found in 3 of 57 (5%) T-ALL patients at diagnosis, I of 14 (7%) patients at relapse and in 12 of 18 (67%) cell lines. All patients with p53 mutations in the course of disease died. Mutations of the p21 gene were not identified in 71 fresh samples and in 18 cell lines. N-RAS mutations were found in 2 of 57 (4%) fresh T-ALL patients at diagnosis, and 4 of 18 cell lines (22%), whereas no mutations were detected in any samples at relapse. Alterations of the p16 gene were found in 18 of 47 (38%) patients at diagnosis and in 7 of 14 (50%) at relapse (not significant). There were no differences in the frequency of alteration of the p16 and p15 genes between event-free patients and the remaining patients. Furthermore, we found the methylation of p16 gene in 3 of 7 patients lacking homozygous deletions, suggesting higher frequency of p16 inactivation than previous reports in T-ALL. Less

Report

(3 results)
  • 1997 Annual Research Report   Final Research Report Summary
  • 1996 Annual Research Report
  • Research Products

    (30 results)

All Other

All Publications (30 results)

  • [Publications] Taki T.et al.: "Fusion of the MLL gene With two different genes, AF6 and AF-5 α, by a complex translocation involving chromosomes 5.6.8.and 11 in infant leukemia." Oncogene. 13. 2121-2130 (1996)

    • Description
      「研究成果報告書概要(和文)」より
    • Related Report
      1997 Final Research Report Summary
  • [Publications] Ohnishi H. et al.: "Homozygous deletions of p16/MTS1 and p15/MS32 in t)1;19)-negative but not in t(1;19)-positive B precursor acute lymphoblastic leukemia in childhood." Leukemia. 10. 1104-1110 (1996)

    • Description
      「研究成果報告書概要(和文)」より
    • Related Report
      1997 Final Research Report Summary
  • [Publications] Taki T.et al.: "Frequency and clinical features of the MLL gene rearrangements in infant leukemia." Leukemia. 10. 1303-1307 (1996)

    • Description
      「研究成果報告書概要(和文)」より
    • Related Report
      1997 Final Research Report Summary
  • [Publications] Ohnishi H.et al.: "Alteration of p16 and p15 genes in acute leukemia with MLL gene rearrangements and their correlation with clinical features." Leukemia. 11. 2120-2124 (1997)

    • Description
      「研究成果報告書概要(和文)」より
    • Related Report
      1997 Final Research Report Summary
  • [Publications] Taki T.et al.: "The t(11;16)(q23;p13)translocation in myelodysplastic syndrome fuses the MLL gene to the CBP gene" Blood. 89. 3945-3950 (1997)

    • Description
      「研究成果報告書概要(和文)」より
    • Related Report
      1997 Final Research Report Summary
  • [Publications] Ida K.et al.: "Adenoviral;E1A-associated protein p300 is involved in acute myeloid leukemia wiht t(11;22)(q23;q13)" Blood. 90. 4699-4704 (1997)

    • Description
      「研究成果報告書概要(和文)」より
    • Related Report
      1997 Final Research Report Summary
  • [Publications] Taki T,Hayashi Y,Hanada R,Taniwaki M,Seto M,Ueda R,Morishita K.: "Fusion of the MLL gene with two different genes, AF6 and AF-5 alpha, by a complex translocation involving chromosomes 5.6.8. and 11 in infant leukemia." Oncogene. 13. 2121-2130 (1996)

    • Description
      「研究成果報告書概要(欧文)」より
    • Related Report
      1997 Final Research Report Summary
  • [Publications] Ohnishi H,Kawamura M,Hanada R,Bessho F,Hayashi Y,et al.: "Homozygous deletions of p16/MTS1 and p15/MTS2 in t (1 ; 19) -negative but not in t (1 ; 19) -positive B precursor acute lymphoblastic leukemia in childhood." Leukemia. 10. 1104-1110 (1996)

    • Description
      「研究成果報告書概要(欧文)」より
    • Related Report
      1997 Final Research Report Summary
  • [Publications] Taki T,Ida K,Hayashi Y,et al.: "Frequency and clinical features of the MLL gene rearrangements in infant leukemia." Leukemia. 10. 1303-1307 (1996)

    • Description
      「研究成果報告書概要(欧文)」より
    • Related Report
      1997 Final Research Report Summary
  • [Publications] Ohnishi H,Guo SX,Ida K,Taki T,Naritaka S,Bessho F,Yanagisawa M,Hanada R,Eguchi M,Kamada N,Kita K,Yamamori S,Hayashi Y.: "Alteration of p16 and p15 genes in acute leukemia with MLL gene rearrangements and their correlation with clinical features." Leukemia. 11. 2120-2124 (1997)

    • Description
      「研究成果報告書概要(欧文)」より
    • Related Report
      1997 Final Research Report Summary
  • [Publications] Taki T., Sako M., Tsuchida M., Hayashi Y.: "The t (11 ; 16) (q23 ; p13) translocation in myelodysplastic syndrome fuses the MLL gene to the CBP gene." Blood. 89. 3945-3950 (1997)

    • Description
      「研究成果報告書概要(欧文)」より
    • Related Report
      1997 Final Research Report Summary
  • [Publications] Ida K., Kitabayashi I., Taki T., Taniwaki M., Noro K., Yamamoto M., Ohki M., Hayashi Y.: "Adenoviral ; E1A-associated protein p300 is involved in acute myeloid leukemia with t (11 ; 22) (q23 ; q13)." Blood. 90. 4699-4704 (1997)

    • Description
      「研究成果報告書概要(欧文)」より
    • Related Report
      1997 Final Research Report Summary
  • [Publications] Takita J, et al.: "Deletion map of chromosome 9 and p16(CDKN2A)gene alterations in neuroblastoma." Cancer Research. 57. 907-912 (1997)

    • Related Report
      1997 Annual Research Report
  • [Publications] Kong X-T., et al.: "Consistent detection of TLS/FUS-ERG chimeric transcripts in acute myeloid leukemia with t(16;21)(p11;q22)and identification of a novel transcript." Blood. 89. 1192-1199 (1997)

    • Related Report
      1997 Annual Research Report
  • [Publications] Yamamoto K, et al.: "Natural history of neuroblastoma found by mass screening." Lancet. 349. 1102 (1997)

    • Related Report
      1997 Annual Research Report
  • [Publications] Kong X-T, et al.: "Expression and mutational analysis of the DCC,DPC4,and MADR2/JV18-1 genesin neuroblastoma." Cancer Research. 57. 3772-3778 (1997)

    • Related Report
      1997 Annual Research Report
  • [Publications] Taki T, et al.: "The t(11;16)(q23;p13)translocation in myelodysplastic syndrome fuses the MLL gene to the CBP gene." Blood. 89. 3945-3950 (1997)

    • Related Report
      1997 Annual Research Report
  • [Publications] Ida K, et al.: "Adenoviral E1A-associated protein p300 is involved in acute myeloid leukemia with t(11;22)(q23;q13)" Blood. 12. 4699-4704 (1997)

    • Related Report
      1997 Annual Research Report
  • [Publications] Tomohiko Taki: "Fusion of the MLL gene with two different genes,AF6 and AF-5α,by a complex translocation involving chromosomes 5,6,8 and 11 in infant leukemia" Oncogene. 13. 2121-2130 (1996)

    • Related Report
      1996 Annual Research Report
  • [Publications] Shigetoshi Kobayashi: "Mutations of the Btk gene in twelve unrelated families with X-linked agammaglobulinemia in Japan:Immunological phenotypes are inconsistent with the location of the mutations" Human Genetics. 97. 424-430 (1996)

    • Related Report
      1996 Annual Research Report
  • [Publications] Hiroaki Ohnishi: "Infreguent mutations of the p53 gene in hepatoblastomas" Gene Chromosomes Cancer. 15. 187-190 (1996)

    • Related Report
      1996 Annual Research Report
  • [Publications] Hiroaki Ohnishi: "Homozygous deletions of p16/HTS1 and p15/MTS2 genes in t(1;19)-negative but not in t(1;19)-positive B precursor acuto lymphoblastic leukemia in chidhood" Leukemia. 10. 1104-1110 (1996)

    • Related Report
      1996 Annual Research Report
  • [Publications] Tomohiko Taki: "Frequency and clinical significance of the MLL gene rearrangemants in infant acute leukemia" Leukemia. 10. 1303-1307 (1996)

    • Related Report
      1996 Annual Research Report
  • [Publications] Kakuda: "A novel human leukaemic cell line,CTS,has a t(6;11) chromosomal translocation and characteristics of pluripotent stem cells" British Journal of Haematology. 95. 306-318 (1996)

    • Related Report
      1996 Annual Research Report
  • [Publications] Yoshiaki Tsuchida: "Genetic clinical markers of human neuroblastoma with special reference to N-myc oncogene:Amplified or not amplitied?-Overview" Tumor Biology. 17. 65-74 (1996)

    • Related Report
      1996 Annual Research Report
  • [Publications] Akira Inoue: "Competitive polymerase chain reaction for the quantification of N-myc gene number in neuroblastoma" Tumor Biology. 17. 262-270 (1996)

    • Related Report
      1996 Annual Research Report
  • [Publications] Atsuhi Ohshima: "11q23 aberation is an additional chromosomal change in de novo acute leukemia after treatment with Etoposide and Mitoxantrone" American Journal of Hematology. 53. 264-266 (1996)

    • Related Report
      1996 Annual Research Report
  • [Publications] Junko Takita: "Deletion map of chromosome 9 and p16 (CDKN2A) gene alterations in neuroblastoma" Cancer Research. 1997年4月(発表予定). (1997)

    • Related Report
      1996 Annual Research Report
  • [Publications] Kohmei Ida: "Detection of chimeric mRNA by reverse transcriptase chain reaction for diagnosis and monitering of acuto leukemi as with 11q23 abnormalities" Medical Pediatric Oncology. (in press).

    • Related Report
      1996 Annual Research Report
  • [Publications] Hirofumi Kobayashi: "Inversion of chromosome 11,inv(11)(p15q22) as a recuring chromosomal aberration associated with dcanovo and secondary myeloid malignancies" Gene Chromosomes Cancer. (in press).

    • Related Report
      1996 Annual Research Report

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Published: 1996-04-01   Modified: 2018-02-02  

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