Analysis of regulatory mechanism of hematopoiesis and exploration of the pathogenesis of hematopoietic neoplasms through comprehensive genetic analysis

2009 Fiscal Year Final Research Report

• Project/Area Number: 17013022
• Research Category: Grant-in-Aid for Scientific Research on Priority Areas
• Allocation Type: Single-year Grants
• Review Section: Biological Sciences
• Research Institution: The University of Tokyo
• Principal Investigator: OGAWA Seishi The University of Tokyo, 医学部附属病院, 特任准教授 (60292900)
• Project Period (FY): 2008 – 2009

Research Abstract

Hematopoietic neoplasms are caused by deregulation of normal components of the hematopoietic system by gene mutations. In fact, many of genetic changes identified as a cause of hematopoietic neoplasms involves those genes implicated in normal regulation of hematopoiesis. In this study, we performed comprehensive genetic analyses of more than 2,000 hematopoietic neoplasms using high-density SNP arrays. We identified a number of genetic alterations involved in the pathogenesis of hematopoietic neoplasms, including gain-of-function mutations of c-CBL in myeloid neoplasms and inactivation mutations of A20 in B-lineage lymphomas, followed by their functional analysis. These findings are thought to contribute not only to our understanding of molecular pathogenesis of hematopoietic cancers, but also to adding our knowledge on regulatory mechanisms of normal hematopoiesis, together with the development of novel diagnostics and therapeutics for these neoplasms.

Research Products

• [Journal Article] Prevalence and prognostic impact of allelic imbalances associated with leukemic transformation of Philadelphia chromosome-negative myeloproliferative neoplasms. (2010)
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  • Journal Title: Blood.
• [Journal Article] SNP array analysis of tyrosine kinase inhibitor-resistant chronic myeloid leukemia identifies heterogeneous secondary genomic alterations. (2010)
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  • Journal Title: Blood. 115 Pages: 1049-1053
• [Journal Article] Hes1 immortalizes committed progenitors and plays a role in blast crisis transition in chronic myelogenous leukemia. (2010)
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• [Journal Article] Derivation of functional mature neutrophils from human embryonic stem cells. (2009)
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  • Journal Title: Blood. 113 Pages: 6584-6592
• [Journal Article] High-resolution genomic copy number profiling of glioblastoma multiforme by single nucleotide polymorphism DNA microarray. (2009)
  • Author(s): Yin D, Ogawa S, Kawamata N, Tunici P, Finocchiaro G, Eoli M, Ruckert C, Huynh T, Liu G, Kato M, Sanada M, Jauch A, Dugas M, Black KL, Koeffler HP.
  • Journal Title: Mol Cancer Res. 7 Pages: 665-677
• [Journal Article] Gain-of-function of mutated C-CBL tumour suppressor in myeloid neoplasms. (2009)
  • Author(s): Sanada M, Suzuki T, Shih LY, Otsu M, Kato M, Yamazaki S, Tamura A, Honda H, Sakata-Yanagimoto M, Kumano K, Oda H, Yamagata T, Takita J, Gotoh N, Nakazaki K, Kawamata N, Onodera M, Nobuyoshi M, Hayashi Y, Harada H, Kurokawa M, Chiba S, Mori H, Ozawa K, Omine M, Hirai H, Nakauchi H, Koeffler HP, Ogawa S
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• [Journal Article] 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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  • Journal Title: Haematologica. 94 Pages: 518-527
• [Journal Article] Gain-of-function mutations and copy number increases of Notch2 in diffuse large B-cell lymphoma. (2009)
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  • Journal Title: Cancer Sci. 100 Pages: 920-926
• [Journal Article] HLA mismatch combinations associated with decreased risk of relapse: implications for the molecular mechanism. (2009)
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  • Journal Title: Blood. 113 Pages: 2851-2858
• [Journal Article] 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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  • Journal Title: Leuk Res. 33 Pages: 569-571
• [Journal Article] Molecular allelokaryotyping of relapsed pediatric acute lymphoblastic leukemia. (2009)
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  • Journal Title: Int J Oncol. 34 Pages: 1603-1612
• [Journal Article] Identified hidden genomic changes in mantle cell lymphoma using high-resolution single nucleotide polymorphism genomic array. (2009)
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  • Journal Title: Exp Hematol. 37 Pages: 937-946
• [Journal Article] Hepatoblastoma in a patient with sotos syndrome. (2009)
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  • Journal Title: J Pediatr. 155 Pages: 937-939
• [Journal Article] Frequent inactivation of A20 in B-cell lymphomas. (2009)
  • Author(s): Kato M, Sanada M, Kato I, Sato Y, Takita J, Takeuchi K, Niwa A, Chen Y, Nakazaki K, Nomoto J, Asakura Y, Muto S, Tamura A, Iio M, Akatsuka Y, Hayashi Y, Mori H, Igarashi T, Kurokawa M, Chiba S, Mori S, Ishikawa Y, Okamoto K, Tobinai K, Nakagama H, Nakahata T, Yoshino T, Kobayashi Y, Ogawa S.
  • Journal Title: Nature. 459 Pages: 712-716
• [Journal Article] HapMap scanning of novel human minor histocompatibility antigens. (2009)
  • Author(s): Kamei M, Nannya Y, Torikai H, Kawase T, Taura K, Inamoto Y, Takahashi T, Yazaki M, Morishima S, Tsujimura K, Miyamura K, Ito T, Togari H, Riddell SR, Kodera Y, Morishima Y, Kuzushima K, Ogawa S, Akatsuka Y.
  • Journal Title: Blood. 113 Pages: 5041-5048
• [Journal Article] Notch activation induces the generation of functional NK cells from human cord blood CD34-positive cells devoid of IL-15. (2009)
  • Author(s): Haraguchi K, Suzuki T, Koyama N, Kumano K, Nakahara F, Matsumoto A, Yokoyama Y, Sakata-Yanagimoto M, Masuda S, Takahashi T, Kamijo A, Takahashi K, Takanashi M, Okuyama Y, Yasutomo K, Sakano S, Yagita H, Kurokawa M, Ogawa S, Chiba S.
  • Journal Title: J Immunol. 182 Pages: 6168-6178
• [Journal Article] Single nucleotide polymorphism genomic arrays analysis of t(8;21) acute myeloid leukemia cells. (2009)
  • Author(s): Akagi T, Shih LY, Ogawa S, Gerss J, Moore SR, Schreck R, Kawamata N, Liang DC, Sanada M, Nannya Y, Deneberg S, Zachariadis V, Nordgren A, Song JH, Dugas M, Lehmann S, Koeffler HP.
  • Journal Title: Haematologica. 94 Pages: 1301-1306
• [Journal Article] Hidden abnormalities and novel classification of t(15;17) acute promyelocytic leukemia (APL) based on genomic alterations. (2009)
  • Author(s): Akagi T, Shih LY, Kato M, Kawamata N, Yamamoto G, Sanada M, Okamoto R, Miller CW, Liang DC, Ogawa S, Koeffler HP.
  • Journal Title: Blood. 113 Pages: 1741-1748
• [Journal Article] Frequent genomic abnormalities in acute myeloid leukemia/myelodysplastic syndrome with normal karyotype. (2009)
  • Author(s): 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.
  • Journal Title: Haematologica. 94 Pages: 213-223
• [Journal Article] Chromosomal abnormalities and novel disease-related regions in progression from Barrett's esophagus to esophageal adenocarcinoma. (2009)
  • Author(s): Akagi T, Ito T, Kato M, Jin Z, Cheng Y, Kan T, Yamamoto G, Olaru A, Kawamata N, Boult J, Soukiasian HJ, Miller CW, Ogawa S, Meltzer SJ, Koeffler HP.
  • Journal Title: Int J Cancer. 125 Pages: 2349-2359
• [Journal Article] (2008)
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  • Journal Title: Biol Blood Marrow Transplant. 14 Pages: 75-87
• [Journal Article] Genome-wide loss of heterozygosity and uniparental disomy in BRCA1/2-associated ovarian carcinomas. (2008)
  • Author(s): Walsh CS, Ogawa S, Scoles DR, Miller CW, Kawamata N, Narod SA, Koeffler HP, Karlan BY.
  • Journal Title: Clin Cancer Res. 14 Pages: 7645-7651
• [Journal Article] ERCC5 is a novel biomarker of ovarian cancer prognosis. (2008)
  • Author(s): Walsh CS, Ogawa S, Karahashi H, Scoles DR, Pavelka JC, Tran H, Miller CW, Kawamata N, Ginther C, Dering J, Sanada M, Nannya Y, Slamon DJ, Koeffler HP, Karlan BY.
  • Journal Title: J Clin Oncol. 26 Pages: 2952-2958
• [Journal Article] Gain of GRHL2 is associated with early recurrence of hepatocellular carcinoma. (2008)
  • Author(s): Tanaka Y, Kanai F, Tada M, Tateishi R, Sanada M, Nannya Y, Ohta M, Asaoka Y, Seto M, Shiina S, Yoshida H, Kawabe T, Yokosuka O, Ogawa S, Omata M.
  • Journal Title: J Hepatol. 49 Pages: 746-757
• [Journal Article] AML1-Evi-1 specifically transforms hematopoietic stem cells through fusion of the entire Evi-1 sequence to AML1. (2008)
  • Author(s): Takeshita M, Ichikawa M, Nitta E, Goyama S, Asai T, Ogawa S, Chiba S, Kurokawa M.
  • Journal Title: Leukemia.
• [Journal Article] Whole-genome profiling of chromosomal aberrations in hepatoblastoma using high-density single-nucleotide polymorphism genotyping microarrays. (2008)
  • Author(s): Suzuki M, Kato M, Yuyan C, Takita J, Sanada M, Nannya Y, Yamamoto G, Takahashi A, Ikeda H, Kuwano H, Ogawa S, Hayashi Y.
  • Journal Title: Cancer Sci. 99 Pages: 564-570
• [Journal Article] Coordinated regulation of transcription factors through Notch2 is an important mediator of mast cell fate. (2008)
  • Author(s): Sakata-Yanagimoto M, Nakagami-Yamaguchi E, Saito T, Kumano K, Yasutomo K, Ogawa S, Kurokawa M, Chiba S.
  • Journal Title: Proc Natl Acad Sci U S A. 105 Pages: 7839-7844
• [Journal Article] Exploration of the genetic basis of GVHD by genetic association studies. (2008)
  • Author(s): 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.
  • Journal Title: Biol Blood Marrow Transplant. 15 Pages: 39-41
• [Journal Article] Integrated analysis of copy number alterations and loss of heterozygosity in human pancreatic cancer using a high-resolution, single nucleotide polymorphism array. (2008)
  • Author(s): 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.
  • Journal Title: Oncology. 75 Pages: 102-112
• [Journal Article] Molecular allelokaryotyping of early-stage, untreated chronic lymphocytic leukemia. (2008)
  • Author(s): Lehmann S, Ogawa S, Raynaud SD, Sanada M, Nannya Y, Ticchioni M, Bastard C, Kawamata N, Koeffler HP.
  • Journal Title: Cancer. 112 Pages: 1296-1305
• [Journal Article] Both Notch1 and Notch2 contribute to the regulation of melanocyte homeostasis. (2008)
  • Author(s): 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.
  • Journal Title: Pigment Cell Research.
• [Journal Article] Identification of human minor histocompatibility antigens based on genetic association with highly parallel genotyping of pooled DNA. (2008)
  • Author(s): 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.
  • Journal Title: Blood. 111 Pages: 3286-3294
• [Journal Article] Cloning of genes involved in chromosomal translocations by high-resolution single nucleotide polymorphism genomic microarray. (2008)
  • Author(s): 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.
  • Journal Title: Proc Natl Acad Sci U S A. 105 Pages: 11921-11926
• [Journal Article] Molecular allelokaryotyping of pediatric acute lymphoblastic leukemias by high-resolution single nucleotide polymorphism oligonucleotide genomic microarray. (2008)
  • Author(s): 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.
  • Journal Title: Blood. 111 Pages: 776-784
• [Journal Article] Genetic profiling of myeloproliferative disorders by single-nucleotide polymorphism oligonucleotide microarray. (2008)
  • Author(s): Kawamata N, Ogawa S, Yamamoto G, Lehmann S, Levine RL, Pikman Y, Nannya Y, Sanada M, Miller CW, Gillil, DG, Koeffler HP.
  • Journal Title: Exp Hematol. 36 Pages: 1471-1479
• [Journal Article] Chronic phase of ETV6-ABL1 positive CML responds to imatinib. (2008)
  • Author(s): Kawamata N, Dashti A, Lu D, Miller B, Koeffler HP, Schreck R, Moore S, Ogawa S.
  • Journal Title: Genes Chromosomes Cancer. 47 Pages: 919-921
• [Journal Article] HapMap scanning of novel human minor histocompatibility antigens. (2008)
  • Author(s): Kamei M, Nannya Y, Torikai H, Kawase T, Taura K, Inamoto Y, Takahashi T, Yazaki M, Morishima S, Tsujimura K, Miyamura K, Ito T, Togari H, Riddell SR, Kodera Y, Morisima Y, Kuzushima K, Ogawa S, Akatsuka Y.
  • Journal Title: Blood.
• [Journal Article] AML1/Runx1 Negatively Regulates Quiescent Hematopoietic Stem Cells in Adult Hematopoiesis. (2008)
  • Author(s): Ichikawa M, Goyama S, Asai T, Kawazu M, Nakagawa M, Takeshita M, Chiba S, Ogawa S, Kurokawa M.
  • Journal Title: J Immunol. 180 Pages: 4402-4408
• [Journal Article] Evi-1 is a critical regulator for hematopoietic stem cells and transformed leukemic cells. (2008)
  • Author(s): Goyama S, Yamamoto G, Shimabe M, Sato T, Ichikawa M, Ogawa S, Chiba S, Kurokawa M.
  • Journal Title: Cell Stem Cell. 3 Pages: 207-220
• [Journal Article] Oncogenic mutations of ALK kinase in neuroblastoma. (2008)
  • Author(s): 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.
  • Journal Title: Nature. 455 Pages: 971-974
• [Journal Article] Therapy of relapsed leukemia after allogeneic hematopoietic cell transplant with T cells specific for minor histocompatibility antigens.
  • Author(s): 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.
  • Journal Title: Blood. (in press)
• [Journal Article] Relapse of leukemia with loss of mismatched HLA due to uniparental disomy following haploidentical hematopoietic stem cell transplantation.
  • Author(s): Villalobos I, Takahashi Y, Akatsuka Y, Muramatsu H, Nishio N, Hama A, Yagasaki H, Saji H, Kato M, Ogawa S, Kojima S.
  • Journal Title: Blood. (in press)
• [Journal Article] Prognostic significance of genetic alterations detected by high-density single nucleotide polymorphism array in gastric cancer.
  • Author(s): 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.
  • Journal Title: Cancer Sci. (in press)
• [Journal Article] CBL mutations in juvenile myelomonocytic leukemia, but not in pediatric myelodysplastic syndrome.
  • Author(s): Shiba N, Kato M, Myoung-ja P, Sanada M, Ito E, Fukushima K, Sako M, Arakawa H, Ogawa S, Hayashi Y.
  • Journal Title: Leukemia. (in press)
• [Journal Article] Genomic profiling of adult acute lymphoblastic leukemia (ALL) by single nucleotide polymorphism oligonucleotide microarray and comparison to pediatric ALL.
  • Author(s): 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.
  • Journal Title: Haematologica. (in press)
• [Journal Article] Deregulated intracellular signaling by mutated c-CBL in myeloid neoplasms.
  • Author(s): Ogawa S, Shih L, Suzuki T, Otsu M, Nakauchi H, Koeffler H, Sanada M.
  • Journal Title: Clinical Cancer Research. (in press)
• [Journal Article] Gain-of-function c-CBL mutations associated with uniparental disomy of 11q in myeloid neoplasms.
  • Author(s): Ogawa S, Sanada M, Shih LY, Suzuki T, Otsu M, Nakauchi H, Koeffler HP.
  • Journal Title: Cell Cycle. (in press)
• [Journal Article] Impact of highly conserved HLA haplotype on acute graft-versus-host disease.
  • Author(s): 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.
  • Journal Title: Blood. (in press)
• [Journal Article] Gastric Cancer Cell Line Hs746T Harbors a Splice Site Mutation of c-Met Causing Juxtamembrane Domain Deletion.
  • Author(s): 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.
  • Journal Title: Biochem Biophys Res Commun. (in press)
• [Remarks]
  • URL: http://www.genome.umin.jp/