The study on the mechanisms of leukemogenesis caused by qualitative and quantitative abnormalities of GATA1 transcription factor

• Project/Area Number: 23390266
• Research Category: Grant-in-Aid for Scientific Research (B)
• Allocation Type: Single-year Grants
• Section: 一般
• Research Field: Pediatrics
• Research Institution: Hirosaki University
• Principal Investigator: ITO ETSURO 弘前大学, 医学(系)研究科(研究院), 教授 (20168339)
• Co-Investigator(Kenkyū-buntansha): TOKI Tsutomu 弘前大学, 大学院医学研究科, 講師 (50195731)
• Project Period (FY): 2011-04-01 – 2014-03-31
• Project Status: Completed (Fiscal Year 2013)
• Budget Amount: ¥19,370,000 (Direct Cost: ¥14,900,000、Indirect Cost: ¥4,470,000); Fiscal Year 2013: ¥5,590,000 (Direct Cost: ¥4,300,000、Indirect Cost: ¥1,290,000); Fiscal Year 2012: ¥5,590,000 (Direct Cost: ¥4,300,000、Indirect Cost: ¥1,290,000); Fiscal Year 2011: ¥8,190,000 (Direct Cost: ¥6,300,000、Indirect Cost: ¥1,890,000)
• Keywords: 小児血液学 / GATA1 / ダウン症 / 白血病 / 21判染色体 / 急性巨核球性白血病 / 転写因子 / ダウン症候群 / 21番染色体 / 巨核球性白血病

Research Abstract

We performed this study to understand the mechanisms of leukemogenesis caused by qualitative and quantitative abnormalities of GATA1, and found the following results.
1. We found the internally deleted regions of GATA1 found in TAM play important roles in megakaryocytic proliferation and perturbation of leukemogenesis. 2. The whole-exome sequencing of DS-AMKL revealed the frequent mutations in the genes coding cohesin components, CTCF, epigenetic regulators, and tyrosine kinases/RAS pathway, which occurred subsequent to GATA1 mutations and might cause malignant transformation from TAM to AMKL.

Research Products

• [Journal Article] Selective expansion of donor-derived regulatory T cells after allogeneic bone marrow transplantation in a patient with IPEX syndrome (2014)
  • Author(s): Horino SSasahara Y, Sato M, Niizuma H, Kumaki S, Abukawa D, Sato A, Imaizumi M, Kanegane H, Kamachi Y, Sasaki S, Terui K, Ito E, Kobayashi I, Ariga T, Tsuchiya S, Kure S
  • Journal Title: Pdeitr Transplant Volume: 18(1) Issue: 1
  • DOI: 10.1111/petr.12184
  • Peer Reviewed
• [Journal Article] The landscape of somatic mutations in Down syndrome-related myeloid disorders. (2013)
  • Author(s): Yoshida K
  • Journal Title: Nature Genet. Volume: 45 Issue: 11 Pages: 1293-1200
  • DOI: 10.1038/ng.2759
  • Peer Reviewed
• [Journal Article] SETBP1 mutations in juvenile myelomonocytic leukaemia and myelodysplastic syndrome but not in paediatric acute myeloid leukaemia (2013)
  • Author(s): Shiba N, Ohki K, Park MJ, Sotomatsu M, Kudo K, Ito E, Sako M, Arakawa H, Hayashi Y
  • Journal Title: Br J Haematol Volume: Epub ahead of print Issue: 1 Pages: 156-159
  • DOI: 10.1111/bjh.12595
  • Peer Reviewed
• [Journal Article] A case of pediatric optic pathway oligodendroglioma presenting widespread invasion and dissemination in the cerebrospinal fluid (2013)
  • Author(s): Katayama K, Asano K, Ohkuma H, Terui K, Sasaki S, Sato T, Ito E, Komori T
  • Journal Title: Brain Tumor Pathol Volume: Epub ahead of print
  • Peer Reviewed
• [Journal Article] Duodenal follicular lymphoma lacks AID but expresses BACH2 and has memory B-cell characteristics (2013)
  • Author(s): Takata K, Sato Y, Nakamura N, Tokunaka M, Miki Y, Yukie Kikuti Y, Igarashi K, Ito E, Harigae H, Kato S, Hayashi E, Oka T, Hoshii Y, Tari A, Okada H, Mohamad AA, Maeda Y, Tanimoto M, Kinoshita T, Yoshino T
  • Journal Title: Mod Pathol Volume: 26(1) Issue: 1 Pages: 22-31
  • DOI: 10.1038/modpathol.2012.127
  • NAID: 130004505772
  • Peer Reviewed
• [Journal Article] Naturally occurring oncogenic GATA1 mutants with internal deletions in transient abnormal myelopoiesis in Down syndrome (2013)
  • Author(s): Toki T, Kanezaki R, Kobayashi E, Kaneko H, Suzuki M, Wang R, Terui K, Kanegane H, Maeda M, Endo M, Mizuochi T, Adachi S, Hayashi Y, Yamamoto M, Shimizu R, Ito E.
  • Journal Title: Blood Volume: 121(16) Issue: 16 Pages: 3181-3184
  • DOI: 10.1182/blood-2012-01-405746
  • Peer Reviewed
• [Journal Article] Clonal selection in xenografted TAM recapitulates the evolutionary process of myeloid leukemia in Down syndrome. (2013)
  • Author(s): Saida, S., K. Watanabe, A. Sato-Otsubo, K. Terui, K. Yoshida, Y. Okuno, T. Toki, R. Wang, Y. Shiraishi, S. Miyano, I. Kato, T. Morishima, H. Fujino, K. Umeda, H. Hiramatsu, S. Adachi, E. Ito, S. Ogawa, M. Ito, T. Nakahata, and T. Heike.
  • Journal Title: Blood Volume: 121 Issue: 21 Pages: 4377-4387
  • DOI: 10.1182/blood-2012-12-474387
  • Peer Reviewed
• [Journal Article] Clinical and genetic characteristics of congenital sideroblastic anemia: comparison with myelodysplastic syndrome with ring sideroblast (MDS-RS) (2013)
  • Author(s): 大場理恵、吉田健一
  • Journal Title: Ann Hematol Volume: 92 Issue: 1 Pages: 1-9
  • DOI: 10.1007/s00277-012-1564-5
  • Peer Reviewed
• [Journal Article] Rabbit antithymocyte globulin and cyclosporine as first-line therapy for children with acquired aplastic anemia (2012)
  • Author(s): Takahashi Y, Muramatsu H, Sakata N, Hyakuna N, Hamamoto K, Kobayashi R, Ito E, Yagasaki H, Ohara A, Kikuchi A, Morimoto A, Yabe H, Kudo K, Watanabe K, Ohga S, Kojima S
  • Journal Title: Blood Volume: 121(5) Issue: 5 Pages: 862-3
  • DOI: 10.1182/blood-2012-11-465633
  • Peer Reviewed
• [Journal Article] Frequent somatic mosaicism of NEMO in T cells of patients with X-linked anhidrotic ectodermal dysplasia with immune- deficiency (2012)
  • Author(s): Kawai T, Imai C et al
  • Journal Title: Blood Volume: 119 Issue: 23 Pages: 5458-66
  • DOI: 10.1182/blood-2011-05-354167
  • Peer Reviewed
• [Journal Article] Identification of TRIB1 R107L gain-of-function mutation in human acute megakaryocytic leukemia (2012)
  • Author(s): Yokoyama T, Toki T, Aoki Y, Kanezaki R, Park MJ, Kanno Y, Takahara T, Yamazaki Y, Ito E, Hayashi Y, Nakamura T.
  • Journal Title: Blood Volume: 119 Issue: 11 Pages: 2608-2611
  • DOI: 10.1182/blood-2010-12-324806
  • Peer Reviewed
• [Journal Article] A novel mutation of ribosomal protein s10 gene in a Japanese patient with diamond-blackfan anemia (2012)
  • Author(s): Yazaki M, Kamei M, Ito Y, Konno Y, Wang R, Toki T, Ito E
  • Journal Title: J Pediatr Hematol Oncol Volume: 34(4) Issue: 4 Pages: 293-5
  • DOI: 10.1097/mph.0b013e31824a20ab
  • Peer Reviewed
• [Journal Article] Frequent somatic mosaicism of NEMO in T cells of patients with X-1 linked anhidrotic ectodermal dysplasia with immunodeficiency (2012)
  • Author(s): Kawai T, Ito E, 他21名
  • Journal Title: Blood Volume: (In press)
  • Peer Reviewed
• [Journal Article] Identification of TRIB1 R107L gain-of-function mutation in human acute megakaryocytic leukemia (2012)
  • Author(s): Yokoyama T, Toki T, Ito E, 他7名
  • Journal Title: Blood Volume: 119(11) Pages: 2608-2611
  • Peer Reviewed
• [Journal Article] Extensive gene deletions in Japanese patients with Diamond-Blackfananemia (2012)
  • Author(s): Kuramitsu M, Toki T, Ito E, 他22名
  • Journal Title: Blood Volume: 119(10) Pages: 2376-84
  • Peer Reviewed
• [Journal Article] Extensive gene deletions in Japanese patients with Diamond-Blackfan anemia (2011)
  • Author(s): Kuramitsu M, Matsubara A, Morio T, Takagi M, Toki T, Terui K, RuNan W, Kanno H, Ohga S, Ohara A, Kitoh T, Sugita K, Kudo K, Matsubayashi T, Mizue N, Ozeki M, Masumi A, Momose H, Takizawa K, Mizukami T, Yamaguchi K, Ogawa S, Ito E, Hamaguchi I
  • Journal Title: Blood Volume: (in press) Issue: 10 Pages: 2376-84
  • DOI: 10.1182/blood-2011-07-368662
  • Peer Reviewed
• [Journal Article] Japan Cord Blood Bank Network. Cord Blood Transplantation from Unrelated Donors for Children with Acute Lymphoblastic Leukemia in Japan : The Impact of Methotrexate on Clinical Outcomes. (2011)
  • Author(s): Kato K, Yoshimi A, Ito E, Oki K, Hara J, Nagatoshi Y, Kikuchi A, Kobayashi R, Nagamura-Inoue T, Kai S, Azuma H, Takanashi M, Isoyama K, Kato S
  • Journal Title: Biol Blood Marrow Transplant. Volume: 17 Issue: 12 Pages: 1814-21
  • DOI: 10.1016/j.bbmt.2011.05.013
  • Peer Reviewed
• [Journal Article] Relapse of aplastic anemia in children after immunosuppressive therapy: a report from the Japan Childhood Aplastic Anemia Study Group (2011)
  • Author(s): Kamio T, Ito E, Ohara A, Kosaka Y, Tsuchida M, Yagasaki H, Mugishima H, Yabe H, Morimoto A, Ohga S, Muramatsu H, Hama A, Kaneko T, Nagasawa M, Kikuta A, Osugi Y, Bessho F, Nakahata T, Tsukimoto I, Kojima S
  • Journal Title: Haematologica Volume: 96(6) Issue: 6 Pages: 814-9
  • DOI: 10.3324/haematol.2010.035600
  • Peer Reviewed
• [Journal Article] Japan Cord Blood Bank Network. Cord blood transplantation from unrelated donors for children with acute lymphoblastic leukemia in Japan : the impact of methotrexate on clinical outcomes (2011)
  • Author(s): Kato K, Ito E, 他12名
  • Journal Title: Biol Blood Marrow Transplant Volume: 17(12) Pages: 1814-21
  • Peer Reviewed
• [Journal Article] Relapse of aplastic anemia in children after immunosuppressive therapy : a report from the Japan Childhood Aplastic Anemia Study Group (2011)
  • Author(s): Kamio T, Ito E, 他18名
  • Journal Title: Haematologica Volume: 96(6) Pages: 814-819
  • Peer Reviewed
• [Journal Article] CD7-positive acute myelomonocytic leukemia with trisomy 21 as a sole acquired chromosomal abnormality in two adolescents (2011)
  • Author(s): Kudo K, Ito E, 他4名
  • Journal Title: Leuk Res Volume: 35(9)
  • Peer Reviewed
• [Presentation] Risk Factors For Clonal Evolution Of Acquired Bone Marrow Failure After Immunosuppressive therapy in Children (2013)
  • Author(s): Hama A, Muramatsu H, Ito M, Kosaka Y, Tsuchida M, Takahashi Y, Kobayashi R, Ito E, Yabe H, Ohga S, Ohara A, Kojima S
  • Organizer: The 55th ASH Annual Meeting and Exposition
  • Place of Presentation: New Orleans, USA
  • Year and Date: 2013-12-07
• [Presentation] 次世代シーケンサーを用いたDown症候群のTAMと急性巨核球性白血病の全エクソン解析(シンポジウム次世代シーケンサーによる小児血液、腫瘍性疾患における研究の進展) (2013)
  • Author(s): 伊藤悦朗
  • Organizer: 第55回日本小児血液・がん学会学術集会
  • Place of Presentation: 福岡
• [Presentation] Genetic basis of myeloid leukemogenesis in Down syndrome (2013)
  • Author(s): Yoshida K, Toki T, Park M, Okuno Y, Shiraishi Y, Sanada M, Kon A, Nagata Y, Sato-Otsubo A, Sato Y, Wang R, Terui K, Kanezaki R, Shiba N, Chiba K, Tanaka H, Hama A, Muramatsu H, Hasegawa D, Nakamura K , Kanegane H, Tsukamoto K, Adachi S, Kawakami K, Kojima S, Izraeli S, Miyano S, Hayashi Y, Ito E, Ogawa S
  • Organizer: 第75回日本血液学会学術集会
  • Place of Presentation: 札幌
• [Presentation] Long-term outcomes of AA or hypoplastic MDS children who received the immunosuppressive therapy (2013)
  • Author(s): Hama A, Muramatsu H, Ito M, Kosaka Y, Tsuchida M, Takahashi Y, Kobayashi R, Ito E, Yabe H, Ohga S, Ohara A, Kojima S
  • Organizer: 第75回日本血(same) 液学会学術集会
  • Place of Presentation: 札幌
• [Presentation] Hematological and morphological characteristics of inherited bone marrow failure syndromes (IBMFS) (2013)
  • Author(s): Hasegawa D, Hama A, Nozawa K, Sakaguchi H, Yabe M, Ito E, Ito M, Kojima S, Nakahata T, Manabe A
  • Organizer: 第75回日本血液学会学術集会
  • Place of Presentation: 札幌
• [Presentation] Identification of a novel causative gene, RPL27, in Diamond-Blackfan Anemia (Diamond-Blackfan貧血における新規原因遺伝子 RPL27の同定) (2013)
  • Author(s): Wang R, Yoshida K, Okuno Y, Sato-Otsubo A, Toki T, Kudo K, Kanezaki R, Shiraishi Y, Chiba K, Terui K, Sato T, Iribe Y, Ohga S, Kuramitsu M, Hamaguchi I, Ohara A, Kamimaki I, Hara J, Sugita K, Matsubara K, Koike K, Ishiguro A, Kawano Y, Kanno H, Kojima S, Sawada T, Uechi T, Kenmochi N, Miyano S, Ogawa S, Ito E
  • Organizer: 第75回日本血液学会学術集会
  • Place of Presentation: 札幌
• [Presentation] Diamond-Blackfan貧血の病因研究の最近の進歩 (2013)
  • Author(s): 伊藤悦朗
  • Organizer: 第116回日本小児科学会学術集会シンポジウム「先天性血液疾患の病態研究に関する最近の進歩」
  • Place of Presentation: 広島
• [Presentation] 次世代シーケンサーを用いたDown症候群のTAMと急性巨核球性白血病の全エクソン解（シンポジウム 次世代シーケンサーによる小児血液、腫瘍性疾患における研究の進展） (2013)
  • Author(s): 伊藤 悦朗
  • Organizer: 第55回日本小児血液・がん学会学術集会
  • Place of Presentation: 福岡
• [Presentation] Genetic basis of myeloid leukemogenesis in Down syndrome. (2013)
  • Author(s): Kenichi Yoshida, Tsutomu Toki, Myoung-ja Park, Yusuke Okuno , Yuichi Shiraishi, et al.
  • Organizer: 第75回日本血液学会学術集会
  • Place of Presentation: 札幌
• [Presentation] Lymphocyte Telomere Length in Pediatric Aplastic Anemia, Refractory Cytopenia of Childhood, and Refractory Cytopenia with Multi-lineage Dysplasia (2012)
  • Author(s): Sakaguchi H, Hama A, Wang X, Narita A, Doisaki S, Muramatsu H, Nakanishi K, Takahashi Y, Tsuchida M, Kobayashi R, Ito E, Yabe H, Ohga S, Ohara A, Hasegawa D, Manabe A, Ito M, Kojima S
  • Organizer: 6th International Symposium on MDS and Bone Marrow Failure Syndromes in Childhood
  • Place of Presentation: Prague, Czech Republic
  • Year and Date: 2012-11-07
• [Presentation] Identification of two new DBA genes, RPS27 and RPL27, by Whole-Exome Sequencing in Diamond-Blackfan Anemia patients (2012)
  • Author(s): Ito E, Yoshida K, Okuno Y, Sato-Otsubo A, Toki T, Miyano S, Shiraishi Y, Chiba K, Terui T, Wang R, Sato T, Iribe Y, Ohga S, Kuramitsu M, Hamaguchi I, Ohara A, Kudo K, Kamimaki I, Hara J, Sugita K, Matsubara K, Koike K, Ishiguro A, Kawano Y, Kanno H, Kojima S and Ogawa S
  • Organizer: 第54回アメリカ血液学会
  • Place of Presentation: アトランタ
• [Presentation] Quantitative or Qualitative Effect of mutant GATA1 factor on Phenotype of Transient Abnormal myelopoiesis (2012)
  • Author(s): Toki T, Ito E
  • Organizer: 第3回JSH国際シンポジウム
  • Place of Presentation: 川越
• [Presentation] Rabbit antithymocyte globulin and cyclosporine as first-line therapy for children with acquired aplastic anemia: a report from the Japan Childhood Aplastic Anemia (AA) Study Group (2012)
  • Author(s): Hamamoto K, Kobayashi R, Ito E, Yagasaki H, Ohara A, Kikuchi A, Morimoto A, Yabe H, Kudo K, Watanabe K, Ohga S, Kojima S, on behalf of the Japan Childhood Aplastic Anemia Study Group
  • Organizer: The 6th International Symposium on MDS and bone marrow failure syndrome in childhood. EWOG MDS
  • Place of Presentation: Prague, Czech Republic
• [Presentation] Allogeneic hematopoietic stem cell transplantation for children with secondary myelodysplastic syndrome after treatment of aplastic anemia in AA-97 study (2012)
  • Author(s): Watanabe K, Kojima Y, Kudo K, Hyakuna N, Kobayashi R, Ito E, Yagasaki E, Ohara A, Kikuchi A, Morimoto A, Yabe H, Ohga S, Nakahata T, Kojima S, on behalf of the Japan Childhood Aplastic Anemia study group
  • Organizer: The 6th International Symposium on MDS and bone marrow failure syndrome in childhood. EWOG MDS
  • Place of Presentation: Prague, Czech Republic
• [Presentation] Telomere Length of Lymphocyte in Pediatric Aplastic Anemia and Refractory Cytopenia of Childhood (2012)
  • Author(s): Sakaguchi H, Hama A, Muramatsu H, Narita A, Doisaki S, Takahashi Y, Tsuchida M, Kobayashi R, Ito E, Yabe H, Ohga S, Ohara A, Hasegawa D, Manabe A, Ito M, Kojima S
  • Organizer: 第74回日本血液学会
  • Place of Presentation: 京都
• [Presentation] Frequent mutations in the RPS17 gene in Japanese DBA Patients (2012)
  • Author(s): Sato T, Kuramitsu M, Matsubara A, Yoshida K, Toki T, Terui K, Wang R, Kanno H, Morio T, Ohga S, Ohara A, Kitoh T, Kudo T, Kojima S, Ogawa S, Hamaguchi I, Ito E
  • Organizer: 第74回日本血液学会
  • Place of Presentation: 京都
• [Presentation] Diamond-Blackfan貧血の病態解明と診断法の進歩(シンポジウム先天性造血障害の病態解明の進歩) (2012)
  • Author(s): 伊藤悦朗
  • Organizer: 第54回日本小児血液・がん学会学術集会
  • Place of Presentation: 横浜
• [Presentation] Expression of the human leukocyte antigenHLA-B61 Common is associated with susceptibility to idiopathic aplastic anemia, hepatitis associated aplastic anemia and fulminant hepatic failure in children with HLA-B61 (2012)
  • Author(s): Takahashi Y, Ohara A, Kobayashi R, Yabe H, Kikuchi A, Yagasaki H, Morimoto A, Watanabe K, Ohga S, Ito E, Kudo K, Fukuda A, Sakamoto S, Kasahara M, Nakazawa A, Kojima S
  • Organizer: 第74回日本血液学会
  • Place of Presentation: 京都
• [Presentation] Genetic Basis of Myeloid Proliferation Related to Down Syndrome (2012)
  • Author(s): Yoshida K, Toki T, Ito E, Ogawa S et al.
  • Organizer: 第54回アメリカ血液学会
  • Place of Presentation: 米国・アトランタ
• [Presentation] Comparison of Clinical Outcome Between Children with Aplastic Anemia and Refractory Cytopenia of Childhood Who Received Immunosuppressive Therapy with Antithymocyte Globulin and Cyclosporine (2011)
  • Author(s): Hama A, Ito E, 他13名
  • Organizer: 全米血液学会
  • Place of Presentation: San Diego, CA, USA
  • Year and Date: 2011-12-11
• [Presentation] GATA1 mutants lacking Rb-binding motif observed in transient abnormal myelopoiesis in Down syndrome (2011)
  • Author(s): Toki T, Ito E, 他12名
  • Organizer: 全米血液学会
  • Place of Presentation: San Diego, CA, USA
  • Year and Date: 2011-12-10
• [Presentation] Lower incidence of CRLF2 rearrangements in Down syndrome-associated acute lymphoblastic leukemia in Japan (2011)
  • Author(s): Hanada I, Toki T, Ito E, 他12名
  • Organizer: 全米血液学会
  • Place of Presentation: San Diego, CA, USA
  • Year and Date: 2011-12-10
• [Presentation] Extensive gene deletions in Japanese patients with Diamond.Blackfan anemia (2011)
  • Author(s): Kuramitsu M, Matsubara A, Morio T, Takagi M, Toki T, Terui K, RuNan Wang, Kanno H, Ohga S, Ohara A, Kojima S, Kitoh T, Goi K, Kudo K, Matsubayashi T, Mizue N, Ozeki M, Masumi A, Momose H, Takizawa K, Mizukami T, Yamaguchi K, Ogawa S, ItoE, Hamaguchi I
  • Organizer: 第73回日本血液学会学術集会
  • Place of Presentation: 名古屋
  • Year and Date: 2011-10-16
• [Presentation] Novel GATA1 mutants with internal deletions in transient abnormal myelopoiesis in Down syndrome (2011)
  • Author(s): Toki T, Kobayashi E, Kanezaki R, Wang RN, Terui K, Kanegane H, Maeda M, Endo M, Mizuochi T, Adachi S, Hayashi Y, Shimizu R, Yamamoto M, and Ito E
  • Organizer: 第73回日本血液学会学術集
  • Place of Presentation: 名古屋
• [Presentation] 先天性赤芽球.(Diamond-Blackfan貧血)の効果的診断法の確立関する研究 (2011)
  • Author(s): 伊藤悦朗,照井君典,土岐力,小島勢二,小原明,大賀正一,森尾友宏,浜口功,倉光球,菅野仁,小川誠司,佐藤亜以子
  • Organizer: 第53回日本小児血液・がん学会学術集会
  • Place of Presentation: 前橋
• [Presentation] 先天性赤芽球瘻(Diamond-Blackfan貧血)の効果的診断法の確立関する研究 (2011)
  • Author(s): 伊藤悦朗, 照井君典, 土岐力, 他8名
  • Organizer: 第53回日本小児血液・がん学会学術集会
  • Place of Presentation: 前橋