造血系の制御機構の解析とゲノム異常の網羅的探索による造血器腫瘍発症機構の解明

• 研究課題/領域番号: 17013022
• 研究種目: 特定領域研究
• 配分区分: 補助金
• 審査区分: 生物系
• 研究機関: 東京大学
• 研究代表者: 小川 誠司 東京大学, 医学部附属病院, 特任准教授 (60292900)
• 研究分担者: 熊野 恵城 東京大学, 医学部・附属病院, 助教 (90396721) ; 鈴木 隆浩 東京大学, 医学部附属病院, 寄附講座教員 (40345210)
• 研究期間 (年度): 2008 – 2009
• 研究課題ステータス: 完了 (2009年度)
• 配分額: 64,000千円 (直接経費: 64,000千円); 2009年度: 12,800千円 (直接経費: 12,800千円); 2008年度: 12,800千円 (直接経費: 12,800千円); 2007年度: 12,800千円 (直接経費: 12,800千円); 2006年度: 12,800千円 (直接経費: 12,800千円); 2005年度: 12,800千円 (直接経費: 12,800千円)
• キーワード: SNPアレイ / 悪性リンパ腫 / ホジキンリンパ腫 / A20 / 11qUPD / 6q23 / 癌抑制遺伝子 / ゲノム解析 / MDS / CMML / c-Cb1 / チロシンキナーゼ / UPD / 造血器腫瘍 / ゲノム / マイクロアレイ / ゲノムコピー数異常 / 高密度オリゴヌクレオチドアレイ / LOH / アレル不均衡 / CNAG / Blimp1 / 造血システム

研究概要

造血器腫瘍は造血系の様々な構成要素の細胞が正常の制御を逸脱することによって生ずる腫瘍性疾患と考えられる。実際、これまでに造血器腫瘍の原因として同定された遺伝子変異の多くが、正常造血において重要な役割を担う遺伝子に生ずる異常であることが知られている。本研究では2000検体を越える多数の造血器腫瘍について高密度SNPアレイによる網羅的なゲノム解析を通じて造血器腫瘍の原因となる遺伝子異常を明らかにすることにより、造血器腫瘍の病態解明を図るとともに造血系の制御機構を明らかにすることを目的として行われた。研究の結果、骨髄系腫瘍におけるc-CBL遺伝子の活性化変異、B細胞悪性リンパ腫におけるA20遺伝子の不活化変異を含む多数の遺伝子変異・ゲノム異常が同定され、これらの変異が腫瘍化に及ぼす効果の詳細が明らかにされた。これらの知見は、造血器腫瘍の病態の理解と正常造血の制御機構の解明に資するとともに、造血器腫瘍の新規治療診断技術の開発に有用であると考えられる。

研究成果

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  • 著者名/発表者名: Nakagawa M, et al.
  • 雑誌名: Blood 108 ページ: 3329-3334
• [雑誌論文] Genomewide screening of DNA copy number changes in chronic myelogenous leukemia with the use of high-resolution array-based comparative genomic hybridization. (2006)
  • 著者名/発表者名: Hosoya N, et al.
  • 雑誌名: Genes Chromosomes Cancer 45 ページ: 482-494
• [雑誌論文] CD1d expression level in tumor cells is an important determinant for anti-tumor immunity by natural killer T cells (2006)
  • 著者名/発表者名: Haraguchi K, et al.
  • 雑誌名: Leuk Lymphoma 47 ページ: 2218-2223
• [雑誌論文] Genome-wide screening of DNA copy number changes in chronic myelogenous leukemia with the use of high-resolution array-based comparative genomic hybridization. (2006)
  • 著者名/発表者名: Hosoya N, Ogawa S, et al.
  • 雑誌名: Genes Chromosomes Cancer 45 ページ: 482-494
• [雑誌論文] A robust algorithm for copy number detection using high-density oligonucleotide single nucleotide polymorphism genotyping arrays. (2005)
  • 著者名/発表者名: Nannya Y, Ogawa S, et al.
  • 雑誌名: Cancer Res. 65 ページ: 6071-6079
• [雑誌論文] Identification of a SRC-like tyrosine kinase gene, FRK, fused with ETV6 in a patient with acute myelogenous leukemia carrying a t(6;12)(q21;p13) translocation. (2005)
  • 著者名/発表者名: Hosoya N, Ogawa S, et al.
  • 雑誌名: Genes Chromosomes Cancer 42 ページ: 269-279
• [雑誌論文] Mutations of the Notch1 gene in T-cell acute lymphoblastic leukemia : analysis in adults and children. (2005)
  • 著者名/発表者名: Lee SY, Ogawa S, et al.
  • 雑誌名: Leukemia 19 ページ: 1841-1843
• [雑誌論文] Hematopoietic stem cells expanded by fibroblast growth factor-1 are excellent targets for retrovirus-mediated gene delivery. (2005)
  • 著者名/発表者名: Crcareva A, Ogawa S, et al.
  • 雑誌名: Exp.Hematol. 33 ページ: 1459-1469
• [雑誌論文] Functional Domains of Runx1 Are Differentially Required for CD4 Repression, TCR{beta} Expression, and CD4/8 Double-Negative to CD4/8 Double-Positive Transition in Thymocyte Development. (2005)
  • 著者名/発表者名: Kawazu M, Ogawa S, et al.
  • 雑誌名: J.Immunol. 174 ページ: 3526-3533
• [雑誌論文] Therapy of relapsed leukemia after allogeneic hematopoietic cell transplant with T cells specific for minor histocompatibility antigens.
  • 著者名/発表者名: Warren EH, Fujii N, Akatsuka Y, Chaney CN, Mito JK, Loeb KR, Gooley TA, Brown ML, Koo KK, Rosinski KV, Ogawa S, Matsubara A, Appelbaum FR, Riddell SR.
  • 雑誌名: Blood. (in press)
• [雑誌論文] Relapse of leukemia with loss of mismatched HLA due to uniparental disomy following haploidentical hematopoietic stem cell transplantation.
  • 著者名/発表者名: Villalobos I, Takahashi Y, Akatsuka Y, Muramatsu H, Nishio N, Hama A, Yagasaki H, Saji H, Kato M, Ogawa S, Kojima S.
  • 雑誌名: Blood. (in press)
• [雑誌論文] Prognostic significance of genetic alterations detected by high-density single nucleotide polymorphism array in gastric cancer.
  • 著者名/発表者名: Tada M, Kanai F, Tanaka Y, Sanada M, Nannya Y, Tateishi K, Ohta M, Asaoka Y, Seto M, Imazeki F, Yoshida H, Ogawa S, Yokosuka O, Omata M.
  • 雑誌名: Cancer Sci. (in press)
  • NAID: 10026592643
• [雑誌論文] CBL mutations in juvenile myelomonocytic leukemia, but not in pediatric myelodysplastic syndrome.
  • 著者名/発表者名: Shiba N, Kato M, Myoung-ja P, Sanada M, Ito E, Fukushima K, Sako M, Arakawa H, Ogawa S, Hayashi Y.
  • 雑誌名: Leukemia. (in press)
• [雑誌論文] Genomic profiling of adult acute lymphoblastic leukemia (ALL) by single nucleotide polymorphism oligonucleotide microarray and comparison to pediatric ALL.
  • 著者名/発表者名: Okamoto R, Ogawa S, Nowak D, Kawamata N, Akagi T, Kato K, Sanada M, Weiss T, Haferlach C, Dugas M, Ruckert C, Haferlach T, Koeffler H.
  • 雑誌名: Haematologica. (in press)
• [雑誌論文] Deregulated intracellular signaling by mutated c-CBL in myeloid neoplasms.
  • 著者名/発表者名: Ogawa S, Shih L, Suzuki T, Otsu M, Nakauchi H, Koeffler H, Sanada M.
  • 雑誌名: Clinical Cancer Research. (in press)
• [雑誌論文] Gain-of-function c-CBL mutations associated with uniparental disomy of 11q in myeloid neoplasms.
  • 著者名/発表者名: Ogawa S, Sanada M, Shih LY, Suzuki T, Otsu M, Nakauchi H, Koeffler HP.
  • 雑誌名: Cell Cycle. (in press)
• [雑誌論文] Impact of highly conserved HLA haplotype on acute graft-versus-host disease.
  • 著者名/発表者名: Morishima S, Ogawa S, Matsubara A, Kawase T, Nannya Y, Kashiwase K, Satake M, Saji H, Inoko H, Kato S, Kodera Y, Sasazuki T, Morishima Y.
  • 雑誌名: Blood. (in press)
• [雑誌論文] Gastric Cancer Cell Line Hs746T Harbors a Splice Site Mutation of c-Met Causing Juxtamembrane Domain Deletion.
  • 著者名/発表者名: Asaoka Y, Toda M, Ikenoue T, Seto M, Imai M, Miyabayashi K, Yamamoto K, Yamamoto S, Kudo Y, Mohri D, Isomura Y, Ijichi H, Tateishi K, Kanai F, Ogawa S, Omata M, Koike K.
  • 雑誌名: Biochem Biophys Res Commun. (in press)
• [学会発表] Genome-wide analysis identifies frequent inactivation of A20 in B-cell malignant lymphomas (2009)
  • 著者名/発表者名: 加藤元博, ら
  • 学会等名: the 14th Congress of the European Hematology Association
  • 発表場所: ベルリン(ドイツ)
  • 年月日: 2009-06-05
• [学会発表] Genome-Wide Analysis of MDS/MPD Disclosed Frequent Homozy gous C-Cb1 mutations Tiahtly Associated with 11a-UPD (2008)
  • 著者名/発表者名: Masashi S
  • 学会等名: 第50回米国血液学会
  • 発表場所: サンフランシスコ
  • 年月日: 2008-12-08
• [学会発表] SNP Chip Analysis of Myelodysplastic Syndromes Disclosed High Frequency of Uniparental Disomy and a Novel Dominant Mutation as the Target of 11q UPD. (2007)
  • 著者名/発表者名: Sanada M, et. al.
  • 学会等名: The 49th Annual Meeting of American Siciety of Hematology
  • 発表場所: 米国アトランタ
  • 年月日: 2007-12-11
• [図書] Method in Molecular Biology 369 Comparative Genomics Volume 2 (2008)
  • 著者名/発表者名: Ogawa S, et. al.
  • 出版者: Humana Press (Editor Nicholas Bergman H)
• [備考]
  • URL: http://www.genome.umin.jp/
• [備考]
  • URL: http://www.genome.umin.ac.jp