Molecular mechanisms of multi-step leukemogenesis in Down syndrome

• Project/Area Number: 17013004
• Research Category: Grant-in-Aid for Scientific Research on Priority Areas
• Allocation Type: Single-year Grants
• Review Section: Biological Sciences
• 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): 土岐 力 弘前大学, 大学院・医学研究科, 講師 (50195731)
• Project Period (FY): 2005 – 2009
• Project Status: Completed (Fiscal Year 2009)
• Budget Amount: ¥47,000,000 (Direct Cost: ¥47,000,000); Fiscal Year 2009: ¥9,400,000 (Direct Cost: ¥9,400,000); Fiscal Year 2008: ¥9,400,000 (Direct Cost: ¥9,400,000); Fiscal Year 2007: ¥9,400,000 (Direct Cost: ¥9,400,000); Fiscal Year 2006: ¥9,400,000 (Direct Cost: ¥9,400,000); Fiscal Year 2005: ¥9,400,000 (Direct Cost: ¥9,400,000)
• Keywords: ダウン症候群 / 白血病 / 転写因子 / GATA1 / 21番染色体 / TMD / WL-DS / BACH1 / STAT3 / KIT / JAK3 / 急性巨核球性白血病 / AML1 / RUNX1 / AMKL

Research Abstract

To understand the mechanism of leukemogensis in Down syndrome, we investigate the genes on chromosome 21 and identified ERG, RUNX1 and BACH1 as the candidates of the causative genes. JAK3 activating mutations were identified in about 10% of preleukemia (TMD) in Down syndrome. GATA1 mutations affected the expression levels of GATA1s protein. GATA1s low mutations in TMD were significantly associated with a risk of progression to acute megakaryoblastic leukemia and lower WBC counts.

Research Products

• [Journal Article] Tenen DG and Kitabayashi I. 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, Shingh H
  • Journal Title: Nature Medicine 16巻 Pages: 580-585
  • Peer Reviewed
• [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 (Epub ahead of print)
  • Peer Reviewed
• [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巻 Pages: 1090-1092
  • Peer Reviewed
• [Journal Article] Voriconazole for both successful treatment of disseminated Trichosporon asahii infection and subsequent cord blood transplantation in an infant with acute myelogenous leukemia. (2010)
  • Author(s): Kudo K, Terui K, Sasaki S, Kamio T, Sato T, Ito E.
  • Journal Title: Bone Marrow Transplant (Epub ahead of print)
  • Peer Reviewed
• [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, Ohoga 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 (Epub ahead of print)
  • 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巻 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巻 Pages: 374-382
  • Peer Reviewed
• [Journal Article] Bach1 deficiency ameliorates hepatic injury in a mouse model. (2009)
  • Author(s): Iida A, Ito E.
  • Journal Title: Tohoku J Exp Med. 217巻 Pages: 223-229
  • NAID: 10025105320
  • 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] 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 cel Is from Down syndrome-related leukemia 0800451GC001 Leukemia (2009)
  • Author(s): Told T. Ito E, et.al.
  • Journal Title: 23 Pages: 95-103
  • Peer Reviewed
• [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, et. al.
  • Journal Title: Haematologica 93巻 Pages: 1591-1593
  • Peer Reviewed
• [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, Ito E, at. al.
  • Journal Title: Brit J Haematol 141巻 Pages: 681-688
  • Peer Reviewed
• [Journal Article] Platelet-derived growth factor may be associated with fibrosis in a Down syndrome patient with transient myeloproliferative disorder. (2008)
  • Author(s): Ogawa J, Kanegane H, Tsuneyama K, Kanezaki R, Futatani T, Nomura K, Ishizawa S, Sasahara M, Ito E, Miyawaki T.
  • Journal Title: Eur J Haematol 81巻 Pages: 58-64
  • Peer Reviewed
• [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
  • Peer Reviewed
• [Journal Article] Functional analysis of JAK3 mutations in transient myeloproliferative disorder and acute megakaryoblastic leukemia accompanying Down syndrome. (2008)
  • Author(s): Sato T, Told T, Kanezald R, Ito E, et.al.
  • Journal Title: Brit J Haematol 141 Pages: 681-688
  • Peer Reviewed
• [Journal Article] Distinct clones are associated with the development of transient myeloproliferative disorder and acute megakaryocytic leukemia in a patient with Down syndrome. (2007)
  • Author(s): Kanegane H, Watanabe S, Nomura K, Gang X, Ito E, Miyawaki T.
  • Journal Title: Int J Hamatol 86巻 Pages: 250-252
  • NAID: 10019798802
  • Peer Reviewed
• [Journal Article] Molecular and clinical characterization of cardio-facio-cutaneous (CFC) syndrome: overlapping clinical manifestations with Costello syndrome. (2007)
  • Author(s): NarumiY, Ito E, et. al.
  • Journal Title: Am J Med Genet A. 143巻 Pages: 799-807
  • Peer Reviewed
• [Journal Article] Distinct clones are associated with the development of transient myeloproliferative disorder and acute megakaryocytic leukemia in a patient with Down Syndrom. (2007)
  • Author(s): Kanegane H, Watanabe S, Nomura K, Gang X, Ito E, Miyawaki T.
  • Journal Title: Int J Hematol 86 Pages: 250-252
  • NAID: 10019798802
  • Peer Reviewed
• [Journal Article] Molecular and clinical characterization of cardio-facio-cutaneous(CFC)syndrome: overlapping clinical manifestations with Costello syndrome. (2007)
  • Author(s): Narumi Y, Ito E, et. al.
  • Journal Title: Am J Med Genet A 143 Pages: 799-807
  • Peer Reviewed
• [Journal Article] Development Acute Megakaryoblastic Leukemia From a Minor Clone in a Down Syndrome Patient With Clinically Overt Transient Myeloproliferative Disorder. (2006)
  • Author(s): Xu G, Kato K, Toki T, Takahashi Y, Terui K, Ito E.
  • Journal Title: J Pediatr Hematol Oncol 28巻 Pages: 696-698
  • Peer Reviewed
• [Journal Article] Cloning and Characterization of the Novel Chimeric Gene p53/FXR2 in the Acute Megakaryoblastic Leukemia Cell Line CMK11-5. (2006)
  • Author(s): Kanezaki R, Toki T, Xu G, Narayanan R, Ito E.
  • Journal Title: Tohoku J Exp Med. 209巻 Pages: 169-180
  • NAID: 10019253497
  • Peer Reviewed
• [Journal Article] Physical association of the patient-specific GATA1 mutants with RUNX1 in acute megakaryoblastic leukemia accompanying Down syndrome. (2006)
  • Author(s): Xu G, Kanezaki R, Toki T, Watanabe S, Takahashi Y, Terui K, Kitabayashi I, Ito E.
  • Journal Title: Leukemia 20巻 Pages: 1002-1008
  • Peer Reviewed
• [Journal Article] Cloning and Charaterization of the novel chimeric gene p53/FXR2 in the acute megakaryoblastic leukemia cell line CMK 11-5 (2006)
  • Author(s): R.Kanezaki, T.Toki, G.Xu, R.Narayanan, E.Ito
  • Journal Title: Tohoku J. Exp. Med 209・3 Pages: 169-180
• [Journal Article] Physical association of the patient-specific GATA1 mutants with RUNX1 in acute megakaryoblastic leukemia accompanying Down syndrome. (2006)
  • Author(s): G.Xu, R.Kanezaki, T.Toki, S.Watanabe, Y.Takahashi, K.Terui, I.Kitabayashi, Ito E.
  • Journal Title: Leukemia 20・6 Pages: 1002-1008
• [Journal Article] Development of Acute Megakaryoblastic Leukemia From a Minor Clone in a Down Syndrome Patient With Clinically Overt Transient Myeloproliferative Disorder (2006)
  • Author(s): Xu G, Kato K, Toki T, Takahashi Y, Terui K, Ito E
  • Journal Title: J Pediatr Hematol Oncol. 28 Pages: 696-698
• [Journal Article] The proto-oncogene ERG in megakaryoblastic leukemias. (2005)
  • Author(s): Rainis L, Toki T, Pimanda JE, Rosenthal E, Machol K, Strehl S, Gottgens B, Ito E, Izraeli S.
  • Journal Title: Cancer Res. 65巻 Pages: 7596-7602
  • Peer Reviewed
• [Journal Article] Transgenic expression of Bach1 transcription factor results in megakaryocytic impairment. (2005)
  • Author(s): Toki T, Katsuoka F, Kanezaki R, Xu G, Kurotaki H, Sun J, Kamio T, Watanabe S, Tandai S, Terui K, Yagihashi S, Komatsu N, Igarashi K, Yamamoto M, Ito E.
  • Journal Title: Blood 105巻 Pages: 3100-3108
• [Journal Article] JAK2 Val617 Pheactivating tyrosine kinase mutation in juvenile myelomonocytic leukemia. (2005)
  • Author(s): Tono C, Xu G, Toki T, Takahashi Y, Sasaki S, Terui K, Ito E.
  • Journal Title: Leukemia 19巻 Pages: 1843-1844
  • Peer Reviewed
• [Journal Article] The proto-oncogene ERG in megakaryoblastic leukemias. (2005)
  • Author(s): Rainis L, Toki T, Pimanda JE, Rosenthal E, Machol K, Strehl S, Gottgens B, Ito E, Izraeli S.
  • Journal Title: Cancer Res 65 Pages: 7596-7602
• [Journal Article] Transgenic expression of Bach1 transcription factor results in megakaryocytic impairment. (2005)
  • Author(s): Toki T, Katusuoka F, Kanezaki R, Xu G, Kurotaki H, Sun J, Kamio T, Watanabe S, Tandai S, Terui K, Yagihashi S, Komatsu N, Igarashi K, Yamamoto M, Ito E.
  • Journal Title: Blood 105 Pages: 3100-3108
• [Journal Article] JAK2 Val617Phe activating tyrosine kinase mutation in juvenile myelomonocytic leukemia (2005)
  • Author(s): Tono C, Xu G, Toki T, Takahashi Y, Sasaki S, Terui K, Ito E.
  • Journal Title: Leukemia 19・10 Pages: 1843-1844
• [Journal Article] Functional analysis of JAK3 mutations in transient myeloproliferative disorder and acute megakaryoblastic leukemia accompanying Down syndrome
  • Author(s): Sato T, Toki T, Ito E, et. al.
  • Journal Title: Brit J Haematol (In press)
• [Presentation] Activating JAK 3 Mutations in Transient Myeloproliferative Disorder and Acute Megakaryoblastic Leukemia Accompanying Down Syndrome (2008)
  • Author(s): Told 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
• [Presentation] Activating JAK3 Mutations in Transient Myeloproliferative Disorder and Acute Megakaryoblastic Leukemia Accompanying Down Syndrome. (2008)
  • Author(s): Toki T, Ito E, et. al.
  • Organizer: The 50th Mnnual meeting of American Society of Hematology
  • Place of Presentation: サンフランシスコ
  • Year and Date: 2008-12-05
• [Presentation] Activating JAK3 Mutations in Transient Myeloproliferative Disorder and Acute Megakaryoblastic Leukemia Accompanying Down Syndrome (2007)
  • Author(s): Sato T, Toki T, Ito E, et. al.
  • Organizer: The 49th Mnnual meeting of American Society of Hematology
  • Place of Presentation: アトランタ(米国)
  • Year and Date: 2007-12-08
• [Presentation] Activating JAK3 mutations in transient myeloproliferative disorder and acute megakaryoblastic leukemia accompanying Down syndrome. (2007)
  • Author(s): Sato T, Toki T, Kanezaki R, Xu G, Terui K, Kamio T, Kiyoi H, Mano H, Ito E.
  • Organizer: The 49th Mnnual meeting of American Society of Hematology
  • Place of Presentation: アトランタ