先端ゲノミクスによる造血器腫瘍の治療・診断標的分子の同定

• 研究課題/領域番号: 20390266
• 研究種目: 基盤研究(B)
• 配分区分: 補助金
• 応募区分: 一般
• 研究分野: 血液内科学
• 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: 半下石 明 東京大学, 医学部附属病院, 特任講師 (20344450) ; 熊野 恵城 東京大学, 医学部附属病院, 助教 (90396721) ; 山本 豪 東京大学, 医学部附属病院, 助教 (70396753)
• 研究期間 (年度): 2009 – 2011
• 研究課題ステータス: 完了 (2010年度)
• 配分額: 18,590千円 (直接経費: 14,300千円、間接経費: 4,290千円); 2010年度: 5,330千円 (直接経費: 4,100千円、間接経費: 1,230千円); 2009年度: 5,850千円 (直接経費: 4,500千円、間接経費: 1,350千円); 2008年度: 7,410千円 (直接経費: 5,700千円、間接経費: 1,710千円)
• キーワード: ゲノミクス / 分子標的 / 造血器腫瘍 / 遺伝子診断 / ゲノム異常 / SNPアレイ / リシーケンス / MDS / ゲノム解析 / 遺伝子変異 / ATL / HTLV-1 / CD2 / CD28 / BCL11B

研究概要

造血器腫瘍はゲノムの変異によって生ずることから、その病態を理解、有効な診断・治療技術を確立するうえで、その原因となっているゲノムの変異を明らかにすることは極めて重要である。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変異やIDH1/2遺伝子の変異、また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た。これらの変異の機能的な解析を含む知見は、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貢献しうるものと考えられる。

研究成果

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• [雑誌論文] A nonsense mutation of IDH1 in myelodysplastic syndromes and related disorders. (2011)
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• [雑誌論文] CBL mutations in juvenile myelomonocytic leukemia and pediatric myelodysplastic syndrome. (2010)
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  • 査読あり
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• [雑誌論文] Genomic profiling of adult acute lymphoblastic leukemia by single nucleotide polymorphism oligonucleotide microarray and comparison to pediatric acute lymphoblastic leukemia. (2010)
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• [雑誌論文] Deregulated Intracellular Signaling by Mutated c-CBL in Myeloid Neoplasms. (2010)
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  • 査読あり
• [雑誌論文] Gain-of-function c-CBL mutations associated with uniparental disomy of 11q in myeloid neoplasms. (2010)
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  • 雑誌名: Cell Cycle. 9
  • 査読あり
• [雑誌論文] SNP array analysis of tyrosine kinase inhibitor-resistant chronic myeloid leukemia identifies heterogeneous secondary genomic alterations. (2010)
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  • 査読あり
• [雑誌論文] Hes1 immortalizes committed progenitors and plays a role in blast crisis transition in chronic myelogenous leukemia. (2010)
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• [雑誌論文] Impact of highly conserved HLA haplotype on acute graft-versus-host disease. (2010)
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• [雑誌論文] The correlation pattern of acquired copy number changes in 164 ETV6/RUNX1-positive childhood acute lymphoblastic leukemias. (2010)
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• [雑誌論文] Gastric cancer cell line Hs746T harbors a splice site mutation of c-Met causing juxtamembrane domain deletion. (2010)
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  • 査読あり
• [雑誌論文] Prevalence and prognostic impact of allelic imbalances associated with leukemic transformation of Philadelphia chromosom e-negative myeloproliferative neoplasms. (2010)
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  • 査読あり
• [雑誌論文] Derivation of functional mature neutrophils from human embryonic stem cells. (2009)
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  • NAID: 120007131544
  • 査読あり
• [雑誌論文] High-resolution genomic copy number profiling of glioblastoma multiforme by single nucleotide polymorphism DNA microarray. (2009)
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  • 査読あり
• [雑誌論文] Gain-of-function of mutated C-CBL tumour suppressor in myeloid neoplasms. (2009)
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  • 雑誌名: Nature. 460 ページ: 904-908
  • 査読あり
• [雑誌論文] Molecular allelokaryotyping of T-cell prolymphocytic leukemia cells with high density single nucleotide polymorphism arrays identifies novel common genomic lesions and acquired uniparental disomy. (2009)
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  • 査読あり
• [雑誌論文] Gain-of-function mutations and copy number increases of Notch2 in diffuse large B-cell lymphoma. (2009)
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  • 雑誌名: Cancer Sci. 100 ページ: 920-926
  • NAID: 10025145854
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• [雑誌論文] HLA mismatch combinations associated with decreased risk of relapse: implications for the molecular mechanism. (2009)
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  • 雑誌名: Blood. 113 ページ: 2851-2858
  • 査読あり
• [雑誌論文] Double minute chromosomes containing MYB gene and NUP214-ABL1 fusion gene in T-cell leukemia detected by single nucleotide polymorphism DNA microarray and fluorescence in situ hybridization. (2009)
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  • 雑誌名: Leuk Res. 33 ページ: 569-571
  • 査読あり
• [雑誌論文] Molecular allelokaryotyping of relapsed pediatric acute lymphoblastic leukemia. (2009)
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  • 雑誌名: Int J Oncol. 34 ページ: 1603-1612
  • 査読あり
• [雑誌論文] Identified hidden genomic changes in mantle cell lymphoma using high-resolution single nucleotide polymorphism genomic array. (2009)
  • 著者名/発表者名: Kawamata N, Ogawa S, Gueller S, Ross SH, Huynh T, Chen J, Chang A, Nabavi-Nouis S, Megrabian N, Siebert R, Martinez-Climent JA, Koeffler HP.
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  • 査読あり
• [雑誌論文] Hepatoblastoma in a patient with sotos syndrome. (2009)
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  • 査読あり
• [雑誌論文] Frequent inactivation of A20 in B-cell lymphomas. (2009)
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  • 雑誌名: Nature. 459 ページ: 712-716
  • NAID: 40019064821
  • 査読あり
• [雑誌論文] HapMap scanning of novel human minor histocompatibility antigens. (2009)
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  • 査読あり
• [雑誌論文] Notch activation induces the generation of functional NK cells from human cord blood CD34-positive cells devoid of IL-15. (2009)
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  • 査読あり
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  • 査読あり
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  • 査読あり
• [雑誌論文] Donor killer immunoglobulin-like receptor (KIR) genotype-patient cognate KIR ligand combination and antithymocyte globulin preadministration are critical factors in outcome of HLA-C-KIR ligand-mismatched T cell-replete unrelated bone marrow transplantation. (2008)
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  • 査読あり
• [雑誌論文] Genome-wide loss of heterozygosity and uniparental disomy in BRCA1/2-associated ovarian carcinomas. (2008)
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  • 雑誌名: J Clin Oncol. 26 ページ: 2952-2958
  • 査読あり
• [雑誌論文] Gain of GRHL2 is associated with early recurrence of hepatocellular carcinoma. (2008)
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  • 雑誌名: J Hepatol. 49 ページ: 746-757
  • 査読あり
• [雑誌論文] AML1-Evi-1 specifically transforms hematopoietic stem cells through fusion of the entire Evi-1 sequence to AML1. (2008)
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  • 雑誌名: Leukemia
  • 査読あり
• [雑誌論文] Whole-genome profiling of chromosomal aberrations in hepatoblastoma using high-density single-nucleotide polymorphism genotyping microarrays. (2008)
  • 著者名/発表者名: Suzuki M, Kato M, Yuyan C, Takita J, Sanada M, Nannya Y, Yamamoto G, Takahashi A, Ikeda H, Kuwano H, Ogawa S, Hayashi Y.
  • 雑誌名: Cancer Sci. 99 ページ: 564-570
  • NAID: 10024003876
  • 査読あり
• [雑誌論文] Characterization of adenocarcinoma of the lung in a familial adenomatous polyposis patient. (2008)
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  • 雑誌名: Pathol Int. 58 ページ: 706-712
  • NAID: 10027378345
  • 査読あり
• [雑誌論文] Coordinated regulation of transcription factors through Notch2 is an important mediator of mast cell fate. (2008)
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  • 雑誌名: Proc Natl Acad Sci USA. 105 ページ: 7839-7844
  • NAID: 120007138253
  • 査読あり
• [雑誌論文] Exploration of the genetic basis of GVHD by genetic association studies. (2008)
  • 著者名/発表者名: Ogawa S, Matsubara A, Onizuka M, Kashiwase K, Sanada M, Kato M, Nannya Y, Akatsuka Y, Satake M, Takita J, Chiba S, Saji H, Maruya E, Inoko H, Morishima Y, Kodera Y, Takehiko S.
  • 雑誌名: Biol Blood Marrow Transplant. 15 ページ: 39-41
  • 査読あり
• [雑誌論文] Integrated analysis of copy number alterations and loss of heterozygosity in human pancreatic cancer using a high-resolution, single nucleotide polymorphism array. (2008)
  • 著者名/発表者名: Lin LJ, Asaoka Y, Tada M, Sanada M, Nannya Y, Tanaka Y, Tateishi K, Ohta M, Seto M, Sasahira N, Kawabe T, Zheng CQ, Kanai F, Ogawa S, Omata M.
  • 雑誌名: Oncology. 75 ページ: 102-112
  • 査読あり
• [雑誌論文] Molecular allelokaryotyping of early-stage, untreated chronic lymphocytic leukemia. (2008)
  • 著者名/発表者名: Lehmann S, Ogawa S, Raynaud SD, Sanada M, Nannya Y, Ticchioni M, Bastard C, Kawamata N, Koeffler HP.
  • 雑誌名: Cancer. 112 ページ: 1296-1305
  • 査読あり
• [雑誌論文] Both Notch1 and Notch2 contribute to the regulation of melanocyte homeostasis. (2008)
  • 著者名/発表者名: Kumano K, Masuda S, Sata M, Saito T, Lee SY, Sakata-Yanagimoto M, Tomita T, Iwatsubo T, Natsugari H, Kurokawa M, Ogawa S, Chiba S.
  • 雑誌名: Pigment Cell Research
  • 査読あり
• [雑誌論文] Identification of human minor histocompatibility antigens based on genetic association with highly parallel genotyping of pooled DNA. (2008)
  • 著者名/発表者名: Kawase T, Nannya Y, Torikai H, Yamamoto G, Onizuka M, Morishima S, Tsujimura K, Miyamura K, Kodera Y, Morishima Y, Takahashi T, Kuzushima K, Ogawa S, Akatsuka Y.
  • 雑誌名: Blood. 111 ページ: 3286-3294
  • 査読あり
• [雑誌論文] Cloning of genes involved in chromosomal translocations by high-resolution single nucleotide polymorphism genomic microarray. (2008)
  • 著者名/発表者名: Kawamata N, Ogawa S, Zimmermann M, Niebuhr B, Stocking C, Sanada M, Hemminki K, Yamatomo G, Nannya Y, Koehler R, Flohr T, Miller CW, Harbott J, Ludwig WD, Stanulla M, Schrappe M, Bartram CR, Koeffler HP.
  • 雑誌名: Proc Natl Acad Sci USA. 105 ページ: 11921-11926
  • 査読あり
• [雑誌論文] Molecular allelokaryotyping of pediatric acute lymphoblastic leukemias by high-resolution single nucleotide polymorphism oligonucleotide genomic microarray. (2008)
  • 著者名/発表者名: Kawamata N, Ogawa S, Zimmermann M, Kato M, Sanada M, Hemminki K, Yamatomo G, Nannya Y, Koehler R, Flohr T, Miller CW, Harbott J, Ludwig WD, Stanulla M, Schrappe M, Bartram CR, Koeffler HP.
  • 雑誌名: Blood. 111 ページ: 776-784
  • 査読あり
• [雑誌論文] Genetic profiling of myeloproliferative disorders by single-nucleotide polymorphism oligonucleotide microarray. (2008)
  • 著者名/発表者名: Kawamata N, Ogawa S, Yamamoto G, Lehmann S, Levine RL, Pikman Y, Nannya Y, Sanada M, Miller CW, Gilliland DG, Koeffler HP.
  • 雑誌名: Exp Hematol. 36 ページ: 1471-1479
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• [雑誌論文] Chronic phase of ETV6-ABL1 positive CML responds to imatinib. (2008)
  • 著者名/発表者名: Kawamata N, Dashti A, Lu D, Miller B, Koeffler HP, Schreck R, Moore S, Ogawa S.
  • 雑誌名: Genes Chromosomes Cancer. 47 ページ: 919-921
  • 査読あり
• [雑誌論文] AML1/Runx1 Negatively Regulates Quiescent Hematopoietic Stem Cells in Adult Hematopoiesis. (2008)
  • 著者名/発表者名: Ichikawa M, Goyama S, Asai T, Kawazu M, Nakagawa M, Takeshita M, Chiba S, Ogawa S, Kurokawa M.
  • 雑誌名: J Immunol. 180 ページ: 4402-4408
  • 査読あり
• [雑誌論文] Evi-1 is a critical regulator for hematopoietic stem cells and transformed leukemic cells. (2008)
  • 著者名/発表者名: Goyama S, Yamamoto G, Shimabe M, Sato T, Ichikawa M, Ogawa S, Chiba S, Kurokawa M.
  • 雑誌名: Cell Stem Cell. 3 ページ: 207-220
  • 査読あり
• [雑誌論文] Oncogenic mutations of ALK kinase in neuroblastoma. (2008)
  • 著者名/発表者名: Chen Y, Takita J, Choi YL, Kato M, Ohira M, Sanada M, Wang L, Soda M, Kikuchi A, Igarashi T, Nakagawara A, Hayashi Y, Mano H, Ogawa S.
  • 雑誌名: Nature. 455 ページ: 971-974
  • 査読あり
• [雑誌論文] Frequent genomic abnormalities in acute myeloid leukemia/myelodysplastic syndrome with normal karyotype. (2008)
  • 著者名/発表者名: Akagi T, Ogawa S, Dugas M, Kawamata N, Yamamoto G, Nannya Y, Sanada M, Miller CW, Yung A, Schnittger S, Haferlach T, Haferlach C, Koeffler HP.
  • 雑誌名: Haematologica. 94 ページ: 213-223
  • 査読あり
• [雑誌論文] Oncogenic mutations of ALK kinase in neuroblastoma (2008)
  • 著者名/発表者名: Chen Y, et al.
  • 雑誌名: Nature 455 ページ: 971-974
  • 査読あり
• [雑誌論文] Cloning of genes involved in chromosomal translocations by high-resolution single nucleotide polymorphism genomic microarray (2008)
  • 著者名/発表者名: Kawamata N, et al.
  • 雑誌名: IProc Natl Acad Sc i U S A 105 ページ: 11921-11926
  • 査読あり
• [雑誌論文] Molecular allelokaryotyping of pediatric acute lymphoblastic leukemias by high-resolution single nucleotide poly morphism oligonucleotide genomic microarray (2008)
  • 著者名/発表者名: Kawamata N, et al.
  • 雑誌名: Blood 111 ページ: 776-784
  • 査読あり
• [雑誌論文] Notch2 signaling is required for proper mast cell distribution and mucosal immunity in the intestine.
  • 著者名/発表者名: Sakata-Yanagimoto M, Sakai T, Miyake Y, Saito T, Maruyama M, Morishita Y, Nakagami-Yamaguchi E, Kumano K, Yagita Y, Fukayama M, Ogawa S, Kurokawa M, Yasutomo K, Chiba S.
  • 雑誌名: Blood In press
  • NAID: 120007137632
  • 査読あり
• [学会発表] Genetic basis of myelodysplastic syndromes and related disorders (2010)
  • 著者名/発表者名: 小川誠司
  • 学会等名: 第72回日本血液学会総会EHA合同シンポジウム
  • 発表場所: パシフィコ横浜会議センター
  • 年月日: 2010-09-26
• [学会発表] Gain-of-function mutations of c-Cb1 tumor suppressor in MDS and MDS/MPD associated with 11q UPD (2009)
  • 著者名/発表者名: 真田昌, 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] 成人T細胞白血病(ATL)における網羅的ゲノム解析 (2008)
  • 著者名/発表者名: 武藤早紀ら
  • 学会等名: 第70回日本血液学会学術集塊
  • 発表場所: 京都
  • 年月日: 2008-10-12
• [備考] ホームページ等
  • URL: http://www.genome.umin.jp/