The molecular mechanisms of transient leukemia by GATA1 mutation and development of molecular target therapy

• Project/Area Number: 20390289
• 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 Hirosaki University, 大学院・医学研究科, 教授 (20168339)
• Co-Investigator(Kenkyū-buntansha): TSUTOMU Toki 弘前大学, 大学院・医学研究科, 講師 (50195731)
• Project Period (FY): 2008 – 2010
• Project Status: Completed (Fiscal Year 2010)
• Budget Amount: ¥18,590,000 (Direct Cost: ¥14,300,000、Indirect Cost: ¥4,290,000); Fiscal Year 2010: ¥5,330,000 (Direct Cost: ¥4,100,000、Indirect Cost: ¥1,230,000); Fiscal Year 2009: ¥5,330,000 (Direct Cost: ¥4,100,000、Indirect Cost: ¥1,230,000); Fiscal Year 2008: ¥7,930,000 (Direct Cost: ¥6,100,000、Indirect Cost: ¥1,830,000)
• Keywords: GATA1 / 一過性白血病 / TAM / ダウン症候群 / 分子標的療法 / 白血病 / 転写因子 / 発現クローニング / GATA1s / 発現量 / ダウン症 / JAK3 / KIT

Research Abstract

We performed this study to understand the role of GATA1 mutations in the development of transient leukemia and develop the molecular target therapy, and found the following results.
1. We found the essential role of SCF/KIT signaling in the proliferation of transient leukemia in Down syndrome.
2. We showed that the mutations in the GATA1 genes affect the expression levels of GATA1s protein. Furthermore, GATA1s low mutations were significantly associated with a risk of progression to ML-DS and lower WBC counts.

Research Products

• [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. 96(6) Pages: 814-819
• [Journal Article] CD7-positive acute myelomonocytic leukemia with trisomy 21 as a sole acquired chromosomal abnormality in two adolescents. (2011)
  • Author(s): Kudo K, Terui K, Sasaki S, MD, Kamio T, Sato T, Ito E
  • Journal Title: Leuk Res. (in press)
• [Journal Article] Voriconazole for both successful treatment of disseminated Trichosporon asahii infection and subsequent cord blood transplantation in an infant with acute myelogenous leukemia. (2011)
  • Author(s): Kudo K, Terui K, MD, Sasaki S, Kamio T, Sato T, Ito E
  • Journal Title: Bone Marrow Transplant. 46(2) Pages: 310-1
• [Journal Article] Molecular pathogenesis in Diamond-Blackfan anemia (review). (2010)
  • Author(s): Ito E, Konno Y, Toki T, Terui K
  • Journal Title: Int J Hematol. 92(3) Pages: 413-8
• [Journal Article] High frequencies of simultaneous FLT3-ITD, WT1, and KIT mutations in hematologic malignancies with NUP98-fusion genes. (2010)
  • Author(s): Taketani T, Taki T, Nakamura T, Kobayashi Y, Ito E, Fukuda S, Yamaguchi S, Hayashi Y
  • Journal Title: Leukemia 24(11) Pages: 1975-7
• [Journal Article] Down syndrome and GATA1 mutations in transient abnormal myeloproliferative disorder: mutation classes correlate with progression to myeloid leukemia. (2010)
  • Author(s): Kanezaki R, Toki T, Terui K, Xu G, Wang RN, Shimada A, Hama A, Kanegane H, Kawakami K, Endo M, Hasegawa D, Kogawa K, Adachi S, Ikeda Y, Iwamoto S, Taga T, Kosaka Y, Kojima S, Hayashi Y, Ito E.
  • Journal Title: Blood 116(22) Pages: 4631-8
• [Journal Article] Guillain-Barre Syndrome minicking acute methotrexate-associated encephalopathy in an adolescent patient with lymphoblastic lymphoma. (2010)
  • Author(s): Terui K, Takahashi Y, Sasaki S, Kudo K, Kamio T, Ito E.
  • Journal Title: J Pediatr Hematol Oncol. 32(8) Pages: 615-6
• [Journal Article] Array-based genomic resequencing of human leukemia. (2010)
  • Author(s): Yamashita Y, Yuan J, Suetake I, Suzuki H, Ishikawa Y, Choi YL, Ueno T, Soda M, Hamada T, Haruta H, Takada S, Miyazaki Y, Kiyoi H, Ito E, Naoe T, Tomonaga M, Toyota M, Tajima S, Iwama A, Mano H
  • Journal Title: Oncogene 29(25) Pages: 3723-31
• [Journal Article] PU.1-mediated upregulation of M-CSFR is critical for MOZ-leukemia stem cell potential. (2010)
  • Author(s): Aikawa Y, Katsumoto T, Zhang P, Shima H, Shino M, Terui K, Ito E, Ohno H, Stanley ER, Singh H, Tenen DG, Kitabayashi I
  • Journal Title: Nature Medicine 16(5) Pages: 580-585
• [Journal Article] Mutations in the ribosomal protein genes in Japanese patients with Diamond-Blackfan anemia. (2010)
  • Author(s): Konno Y, Toki T, Tandai S, Xu G, Wang RN, Terui K, Ohga S, Hara T, Hama A, Kojima S, Hasegawa D, Kosaka Y, Yanagisawa R, Koike K, Kanai R, Imai T, Hongo T, Park MJ, Sugita K, Ito E
  • Journal Title: Haematologica 95(8) Pages: 1293-9
• [Journal Article] CBL mutations in juvenile myelomonocytic leukemia and pediatric myelodysplastic syndrome. (2010)
  • Author(s): Shiba N, Kato NM, Park MJ, Sanada M, Ito E, Fukushima K, Sako M, Arakawa H, Ogawa S, Hayashi Y
  • Journal Title: Leukemia 24(5) Pages: 1090-1092
• [Journal Article] Down syn(kome and GATAl mutations in transient abnormal myeloproliferative di sorder : mutation classes correlate with progression to myeloid leukemia. (2010)
  • Author(s): Kanezaki R, Told T, Ito E, et al.
  • Journal Title: Blood Volume: 116(22) Pages: 4631-4638
  • Peer Reviewed
• [Journal Article] PU.1-mediated upregulation of M-CSFR is critical for MOZ-leukemia stem cell potential. (2010)
  • Author(s): Yamashita Y, Ito E, et al.
  • Journal Title: Nature Medicine Volume: 16(5) Pages: 580-585
  • Peer Reviewed
• [Journal Article] Array-based genomic resequencing of human leukemia (2010)
  • Author(s): Yamashita Y, Ito E, et al.
  • Journal Title: Oncogene Volume: 29(25) Pages: 3723-3731
  • Peer Reviewed
• [Journal Article] Mutations in the ribosomal protein genes in Japanese patients with Diamond-Blac kfan anemia. (2010)
  • Author(s): Komo Y, Tbki T, Ito E, 他
  • Journal Title: Haematologica Volume: 95(8) Pages: 1293-1299
  • Peer Reviewed
• [Journal Article] High frequencies of simultaneous FLT3-ITD, WTI, and KIT mutations in hematol ogic malignancies with NUP98-fusion genes. (2010)
  • Author(s): Taketami T, Ito E, Hayashi Y, 他
  • Journal Title: Leukemia Volume: 24(11) Pages: 1975-1977
  • Peer Reviewed
• [Journal Article] CBL mutations in juvenile myelomonocytic leukemia and pediatric myelodysplastic syndrome. (2010)
  • Author(s): Shiba N, Ito E, Hayashi Y, 他
  • Journal Title: Leukemia Volume: 24(5) Pages: 1090-1092
  • Peer Reviewed
• [Journal Article] Molecular pathogenesis in Diamond-Blackfan anemia (2010)
  • Author(s): Ito E, Konno Y, Toki T, Terui K.
  • Journal Title: Int J Haematol Volume: 92(3) Pages: 413-418
  • NAID: 10027673188
  • Peer Reviewed
• [Journal Article] Survival after cord blood transplantation from unrelated donor as a second hematopoietic stem cell transplantation for recurrent pediatric acute myeloid leukemia. (2009)
  • Author(s): Oda M, Isoyama K, Ito E, Inoue M, Tsuchida M, Kigasawa H, Kato K, Kato S
  • Journal Title: Int J Hematol. 89 Pages: 374-82
• [Journal Article] Bach1 deficiency ameliorates hepatic injury in a mouse model. (2009)
  • Author(s): Iida A, Inagaki K, Miyazaki A, Yonemori F, Ito E, Igarashi K
  • Journal Title: Tohoku J Exp Med. 217 Pages: 223-229
  • NAID: 10025105320
• [Journal Article] Successful umbilical cord blood transplantation for intractable eczematous eruption in hypohidrotic ectodermal dysplasia with immunodeficiency. (2009)
  • Author(s): Minakawa S, Takeda H, Nakano H, Tono C, Takahashi Y, Sasaki S, Terui K, Ito E, Sawamura D
  • Journal Title: Clin Exp Dermatol. 34(7)
• [Journal Article] The key role of stem cell factor/KIT signaling in the proliferation of blast cells from Down syndrome-related leukemia. (2009)
  • Author(s): Toki T, Kanezaki R, Adachi S, Fujino H, Xu G, Sato T, Suzuki K, Tauchi H, Endo M, Ito E
  • Journal Title: Leukemia 23 Pages: 95-103
• [Journal Article] The key role of stem cell factor/KIT signaling in the proliferation of blast cells from Down syndrome-related leukemia. (2009)
  • Author(s): Toki T, Ito E, et al.
  • Journal Title: Leukemia 23 Pages: 95-103
  • Peer Reviewed
• [Journal Article] Survival after cord blood transplantation from unrelated donor as a second hematopoietic stem cell transplantation for recurrent pediatric acute myeloid leukemia. (2009)
  • Author(s): Oda M, Ito E, et al.
  • Journal Title: Int J Hematol. 89 Pages: 374-382
  • Peer Reviewed
• [Journal Article] Bachl deficiency ameliorates hepatic injury in a mouse model. (2009)
  • Author(s): Iida A, Ito E, et al.
  • Journal Title: Tohoku J Exp Med. 217 Pages: 223-229
  • Peer Reviewed
• [Journal Article] The key role of stem cell factor/KIT signaling in the proliferation of blast cells from Down syndrome-related leukemia (2009)
  • Author(s): Toki T Ito E, et.al.
  • Journal Title: Leukemia 23 Pages: 95-103
  • Peer Reviewed
• [Journal Article] Juvenile myelomonocytic leukemia presenting multiple painful erythematous lesions diagnosed as Sweet's syndrome. (2008)
  • Author(s): Kitamura H, Kaneko T, Nakano H, Terui K, Ito E, Sawamura D
  • Journal Title: J Dermatol. 35 Pages: 368-370
  • NAID: 10024297132
• [Journal Article] Two novel variants of MOZ-CBP fusion transcripts in spontaneously remitted infant leukemia with t(1;16;8)(p13;p13;p11), a new variant of t(8;16)(p11;p13). (2008)
  • Author(s): Terui K, Sato T, Sasaki S, Kudo K, Kamio T, Ito E
  • Journal Title: Haematologica. 93 Pages: 1591-1593
• [Journal Article] Functional analysis of JAK3 mutations in transient myeloproliferative disorder and acute megakaryoblastic leukemia accompanying Down syndrome. (2008)
  • Author(s): Sato T, Toki T, Kanezaki R, Xu G, Terui K, Kanegane H, Miura M, Adachi S, Migita M, Morinaga S, Nakano T, Endo M, Kojima S, Kiyoi H, Mano H, Ito E
  • Journal Title: Brit J Haematol. 141 Pages: 681-688
• [Journal Article] Two novel variants of MOZ-CBP fusion transcripts in spontaneously remitted infant leukemia with t(1 ; 16 ; 8)(p13 ; p13 ; p11), a new variant of t(8 ; 16)(p11 ; p13) (2008)
  • Author(s): Terui K, Sato T, Sasaki S, KudoK, Kamio T, Ito E.
  • Journal Title: Haematologica 93 Pages: 1591-1593
  • Peer Reviewed
• [Journal Article] Functional analysis of JAK3 mutations in transient myeloproliferative disorder order and acute megakaryoblastic leukemia accompanying Down syndrome (2008)
  • Author(s): Sato T, Toki T, Kanezaki R, Ito E, et.al.
  • Journal Title: But J Haematol 141 Pages: 681-688
  • Peer Reviewed
• [Presentation] Transient abnormal myelopoiesis and acute myeloid leukemia in Down syndrome(Presidential Symposium : Recent Advance in Pediatric Hemablogy) (2010)
  • Author(s): Ito E, Tloki T
  • Organizer: 日本小児血液学会
  • Place of Presentation: 大阪国際会議場、大阪
  • Year and Date: 2010-12-19
• [Presentation] TAMの分子診断(シンポジウム:小児血液疾患の分子診断の進歩とその臨床応用) (2010)
  • Author(s): 伊藤悦朗、照井君典、土岐力
  • Organizer: 第113回日本小児科学会学術集会
  • Place of Presentation: 盛岡市
• [Presentation] Transient abnormal myelopoiesis and acute myeloid leukemia in Down syndrome(血液プレジデンシャルシンポジウム) (2010)
  • Author(s): 伊藤悦朗, 土岐力
  • Organizer: 第52回日本小児血液学会総会
  • Place of Presentation: 大阪国際会議場、大阪市
• [Presentation] Down syndrome and GATA1 mutations in transient abnormal myeloproliferative disorder : mutation classes affect the phenotype of the disorder. (2010)
  • Author(s): Etsuro Ito, Rika Kanezaki, Kiminori Terui, RuNan Wang, Tsutomu Toki
  • Organizer: 5^<th> International Symposium on GATA factors (9^<th> Japanese Biochimical Society (JBS) Bio-Frontier Symposium 2010).
  • Place of Presentation: Gonryo-Hall, Sendai
• [Presentation] Ribosomal proteinと赤血球産生障害(Diamond-Blackfan anemia群と5q欠失症候群) (2009)
  • Author(s): 伊藤悦朗
  • Organizer: 第71回日本血液学会
  • Place of Presentation: 京都国際会議場、京都(教育講演)
• [Presentation] Activating JAK3 Mutations in Transient Myeloprolifetative Disorder and Acute Megalcaryoblastic Leukemia Accompanying Down Syndrome (2008)
  • Author(s): Toki T, Ito E, et.al.
  • Organizer: The 50^<th> Mnnual meeting of American Society of HematologY
  • Place of Presentation: サンフランシスコ(米国)
  • Year and Date: 2008-12-08
• [Book] 血液診療エキスパート貧血 (2010)
  • Author(s): 伊藤悦朗
  • Total Pages: 253
  • Publisher: 中外医学社
• [Remarks] ホームページ等
  • URL: http://www.a-onclick.com/hirodai_syonika/
• [Remarks]
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