Analysis on genetic basis of leukemia relapse and therapy resistance

• Project/Area Number: 23249052
• Research Category: Grant-in-Aid for Scientific Research (A)
• Allocation Type: Single-year Grants
• Section: 一般
• Research Field: Hematology
• Research Institution: Kyoto University (2013); The University of Tokyo (2011-2012)
• Principal Investigator: OGAWA SEISHi 京都大学, 医学(系)研究科(研究院), 教授 (60292900)
• Project Period (FY): 2011-04-01 – 2014-03-31
• Project Status: Completed (Fiscal Year 2013)
• Budget Amount: ¥47,970,000 (Direct Cost: ¥36,900,000、Indirect Cost: ¥11,070,000); Fiscal Year 2013: ¥9,230,000 (Direct Cost: ¥7,100,000、Indirect Cost: ¥2,130,000); Fiscal Year 2012: ¥18,460,000 (Direct Cost: ¥14,200,000、Indirect Cost: ¥4,260,000); Fiscal Year 2011: ¥20,280,000 (Direct Cost: ¥15,600,000、Indirect Cost: ¥4,680,000)
• Keywords: 白血病 / 幹細胞 / リシーケンス / 遺伝子変異 / エピゲノム / 高速シーケンス / 再発 / 難治性白血病 / ゲノム / エクソーム解析 / エピゲノム解析 / 大量並列シーケンス / RNAスプライシング / 治療抵抗性 / 全ゲノム解析

Research Abstract

During the past two decades, significant advance has been made in therapeutics of leukemia. However, overall cure rates for many leukemia types have been less than 50%. In this study, to reveal genetic basis for relapsed or therapy-resistant leukemias, we performed comprehensive mutation studies for different types of leukemia, followed by targeted deep sequencing of newly identified as well as common mutational targets, using massively parallel sequencing in large cohorts of leukemias. We identified a number of new mutational targets, including multiple components of the cohesion complex and the RNA splicing machinery as well as SETBP1, DDX41, and DNA repair genes, many of which were associated with poor clinical outcomes. We further demonstrated that information of mutational status of multiple mutational targets could be used for better prediction of the clinical outcome of patients with AML, enabling their stratification for choice of therapeutics.

Research Products

• [Journal Article] Haploinsufficiency of Sf3b1 leads to compromised stem cell function but not to myelodysplasia. (2014)
  • Author(s): Matsunawa M, Yoshida K
  • Journal Title: Leukemia Volume: (Epub ahead of print) Issue: 9 Pages: 1-7
  • DOI: 10.1038/leu.2014.73
  • Peer Reviewed / Open Access
• [Journal Article] Landscape of genetic lesions in 944 patients with myel odysplastic syndromes. (2014)
  • Author(s): Haferlach T, Nagata Y, Grossmann V, Okuno Y, Bacher U, Nagae G, Schnittger S, Sanada M, Kon A, Alpermann T, Yoshida K, Roller A, Nadarajah N, Shiraishi Y, Shiozawa Y, Chiba K, Tanaka H, Koeffler HP, Klein HU, Dugas M, Aburatani H, Kohlmann A, Miyano S, Haferlach C, Kern W, Ogawa S.
  • Journal Title: Leukemia Volume: 28(2) Issue: 2 Pages: 241-7
  • DOI: 10.1038/leu.2013.336
  • Peer Reviewed
• [Journal Article] Comprehensive analysis of genetic alterations and their prognostic impacts in adult acute myeloid leukemia patients (2014)
  • Author(s): Kihara R, S. Ogawa, S. (32/33) Naoe, T.
  • Journal Title: Leukemia Volume: inpress Issue: 8 Pages: 1586-95
  • DOI: 10.1038/leu.2014.55
  • 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] Exome sequencing identifies secondary mutations of SETBP1 and JAK3 in juvenile myelomonocytic leukemia. (2013)
  • Author(s): Sakaguchi H, Yoshida K
  • Journal Title: Nature Genet. Volume: 46 Issue: 8 Pages: 937-941
  • DOI: 10.1038/ng.2698
  • Peer Reviewed
• [Journal Article] Concurrent loss of Ezh2 and Tet2 cooperates in the pathogenesis of myelodysplastic disorders. (2013)
  • Author(s): Muto T, Sashida G, Oshima M, Wendt GR, Mochizuki-Kashio M, Nagata Y, Sanada M, Miyagi S, Saraya A, Kamio A, Nagae G, Nakaseko C, Yokote K, Shimoda K, Koseki H, Suzuki Y, Sugano S, Aburatani H, Ogawa S, Iwama A.
  • Journal Title: The Journal of Experimental Medicine Volume: 210(12) Issue: 12 Pages: 2627-39
  • DOI: 10.1084/jem.20131144
  • Peer Reviewed
• [Journal Article] Somatic SETBP1 mutations in myeloid malignancies. (2013)
  • Author(s): Makishima H, Yoshida K
  • Journal Title: Nature Genet. Volume: 45 Issue: 8 Pages: 942-946
  • DOI: 10.1038/ng.2696
  • Peer Reviewed
• [Journal Article] Recurrent mutations in multiple components of the cohesin complex in myeloid neoplasms. (2013)
  • Author(s): Kon A, Yoshida K
  • Journal Title: Nature Genet. Volume: 45 Issue: 10 Pages: 1232-1237
  • DOI: 10.1038/ng.2731
  • 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] ACTN1 Mutations Cause Congenital Macrothrombocytopenia (2013)
  • Author(s): 國島伸治、吉田健一
  • Journal Title: Am J Hum Genet Volume: 92 Issue: 3 Pages: 431-438
  • DOI: 10.1016/j.ajhg.2013.01.015
  • Peer Reviewed
• [Journal Article] An empirical Bayesian framework for somatic mutation detection from cancer genome sequencing data (2013)
  • Author(s): Yuichi Shiraishi
  • Journal Title: Nucleic Acid Research Volume: 41 Issue: 7 Pages: e89-e89
  • DOI: 10.1093/nar/gkt126
  • Peer Reviewed
• [Journal Article] Novel splicing-factor mutations in juvenile myelomonocytic leukemia (2012)
  • Author(s): 滝田順子、吉田健一
  • Journal Title: Leukemia Volume: 26 Issue: 8 Pages: 1879-1881
  • DOI: 10.1038/leu.2012.45
  • Peer Reviewed
• [Journal Article] KIF5B-RET fusions in lung adenocarcinoma (2012)
  • Author(s): Takashi Kohno
  • Journal Title: Nature Medicine Volume: 18 Issue: 3 Pages: 375-7
  • DOI: 10.1038/nm.2644
  • Peer Reviewed
• [Journal Article] Polycomb-Mediated Loss of miR-31 Activates NIK-dependent NF-κB Pathway in Adult T-cell Leukemia and Other Cancers (2012)
  • Author(s): Yamagishi M, Uchimaru K, et al.
  • Journal Title: Cancer cell Volume: 21 Issue: 1 Pages: 121-135
  • DOI: 10.1016/j.ccr.2011.12.015
  • Peer Reviewed
• [Journal Article] Novel splicing-factor mutations in juvenile myelomonocytic leukemia (2012)
  • Author(s): Takita J, Yoshida K, Sanada M, Nishimura R, Okubo J, Motomura A, Hiwatari M, Oki K, Igarashi T, Hayashi Y, Ogawa S
  • Journal Title: Leukemia
  • Peer Reviewed
• [Journal Article] Polycomb-Mediated Loss of miR-31 Activates NIK-Dependent NF-kap paB Pathway in Adult T Cell Leukemia and Other Cancers (2011)
  • Author(s): Yamagishi M, Nakano K, Miyake A, Yamochi T, Kagami Y, Tsutsiuni A, Matsuda Y, Sato-Otsubo A, Muto S, Utsunomiya A, Yamaguchi K, Uchimaru K, Ogawa S, Watanabe T
  • Journal Title: Cancer cell Volume: 21 Pages: 121-135
  • Peer Reviewed
• [Journal Article] Aberrant activation of ALK kinase by a novel truncated form ALK protein in neuroblastoma (2011)
  • Author(s): Okubo J, Takita J, Chen Y, Oki K, Nishimura R, Kato M, Sanada M, Hiwatari M, Hayashi Y, Igarashi T, Ogawa S
  • Journal Title: Oncogene
  • Peer Reviewed
• [Journal Article] Frequent pathway mutations of splicing machinery in myelodysplasia (2011)
  • Author(s): Yoshida K, Sanada M, Shiraishi Y, Nowak D, Nagata Y, Yamamoto R, Sato Y, Sato-Otsubo A, Kon A, Nagasaki M, Chalkidis G, Suzuki Y, Shiosaka M, Kawahata R, Yamaguchi T, Otsu M, Obara N, Sakata-Yanagimoto M, Ishiyama K, Mori H, Nolte F, Hofmann WK, Miyawaki S, Sugano S, Haferlach C, Koeffler HP, Shih LY, Haferlach T, Chiba S, Nakauchi H, Miyano S, Ogawa S
  • Journal Title: Nature Volume: 478 Pages: 64-69
  • Peer Reviewed
• [Journal Article] A nonsense mutation of IDH1 in myelodysplastic syndromes and related disorders (2011)
  • Author(s): Yoshida K, Sanada M, Kato M, Kawahata R, Matsubara A, Takita J, Shih LY, Mori H, Koeffler HP, Ogawa S
  • Journal Title: Leukemia Volume: 25 Pages: 184-186
  • Peer Reviewed
• [Journal Article] Hayashi Y.CBL mutations in infant acute lymphoblastic leukaemia (2011)
  • Author(s): Shiba N, Park MJ, Taki T, Takita J, Hiwatari M, Kanazawa T, Sotomatsu M, Ishii E, Arakawa H, Ogawa S
  • Journal Title: Br J Haematol Volume: 156(5) Pages: 672-674
  • Peer Reviewed
• [Journal Article] Polycomb-Mediated Loss of miR-31 Activates NIK-Dependent NF-kap paB Pathway in Adult T Cell Leukemia and Other Cancers (2011)
  • Author(s): Yamagishi M, Nakano K, Miyake A, Yamochi T, Kagami Y, Tsutsiuni A, Matsuda Y, Sato-Otsubo A, Muto S, Utsunomiya A, Yamaguchi K, Uchimaru K, Ogawa S, Watanabe T
  • Journal Title: Cancer cell. Volume: 21 Pages: 121-135
  • Peer Reviewed
• [Journal Article] Frequent pathway mutations of splicing machinery in myelodysplasia (2011)
  • Author(s): Yoshida K, Sanada M, Shiraishi Y, Nowak D, Nagata Y, Yamamoto R, Sato Y, Sato-Otsubo A, Kon A, Nagasaki M, Chalkidis G, Suzuki Y, Shiosaka M, Kawahata R, Yamaguchi T, Otsu M, Obara N, Sakata-Yanagimoto M, Ishiyama K, Mori H, Nolte F, Hofmann WK, Miyawaki S, Sugano S, Haferlach C, Koeffler HP, Shih LY, Haferlach T, Chiba S, Nakauchi H, Miyano S, Ogawa S
  • Journal Title: Nature. Volume: 478 Pages: 64-69
  • Peer Reviewed
• [Presentation] Recurrent somatic SETBP1 mutations in myeloid neoplasms (2013)
  • Author(s): Ayana Kon, Ogawa S., et al
  • Organizer: 第72回日本癌学会学術総会
  • Place of Presentation: 横浜
  • Year and Date: 2013-10-05
• [Presentation] Recurrent somatic SETBP1 mutations in myeloid neoplasms (2013)
  • Author(s): Ayana Kon, Ogawa S., et al
  • Organizer: 第75回日本血液学会学術集会
  • Place of Presentation: 北海道
  • Year and Date: 2013-10-01
• [Presentation] Comprehensive genome analysis of pediatric myeloid neoplasms (2013)
  • Author(s): Ogawa S., et al
  • Organizer: 18th Congress of EHA
  • Place of Presentation: Stockholm(Sweden)
  • Year and Date: 2013-06-15
• [Presentation] RE-CLASSIFICATION OF ADULT ACUTE MYELOID LEUKEMIA BASED ON THE COMPREHENSIVE GENETIC ANALYSIS (2013)
  • Author(s): Kihara R, Ogawa S., et al
  • Organizer: 18th Congress of EHA
  • Place of Presentation: Stockholm(Sweden)
  • Year and Date: 2013-06-14
• [Presentation] Recent advance in molecular genetics of MDS as revealed by massively parallel sequencing (2013)
  • Author(s): Ogawa S., et al
  • Organizer: 18th Congress of EHA
  • Place of Presentation: Stockholm(Sweden)
  • Year and Date: 2013-06-13
• [Presentation] Recurrent pathway mutations of multiple components of cohesin complex in myeloid neoplasms (2013)
  • Author(s): Ayana Kon, Ogawa S., et al
  • Organizer: AACR Annual meeting
  • Place of Presentation: Washington, DC (USA)
  • Year and Date: 2013-04-09
• [Presentation] Genetic analysis of myelodysplastic syndromes (2013)
  • Author(s): Seishi Ogawa
  • Organizer: The 2013 Joint Symposium : multi-Omics in KSBMB WinterWorkshop
  • Place of Presentation: High-One Resort, (Korea )
  • Year and Date: 2013-01-16
• [Presentation] Recurrent pathway mutations of multiple components of cohesin complex in myeloid neoplasms (2013)
  • Author(s): Ayana Kon, Ogawa S. et al.
  • Organizer: AACR Annual meeting 2013
  • Place of Presentation: Washington, DC (USA)
  • Invited
• [Presentation] RE-CLASSIFICATION OF ADULT ACUTE MYELOID LEUKEMIA BASED ON THE COMPREHENSIVE GENETIC ANALYSIS. (2013)
  • Author(s): Kihara R, Ogawa S. et al.
  • Organizer: 18th Congress of EHA
  • Place of Presentation: Stockholm(Sweden)
  • Invited
• [Presentation] Landscape of genetic lesions in 944 patients with Myelodysplastic syndromes (2013)
  • Author(s): 永田安伸, 小川誠司, et al.
  • Organizer: 第75回日本血液学会学術集会
  • Place of Presentation: 北海道
  • Invited
• [Presentation] Genetic analysis of myelodysplastic syndromes (2013)
  • Author(s): Seishi Ogawa
  • Organizer: The 2013 Joint Symposium: multi-Omics in KSBMB Winter Workshop
  • Place of Presentation: High-One Resort, Korea
  • Invited
• [Presentation] Pathway Mutations in the Splicing Machinery in Myeloid Neoplasms (2012)
  • Author(s): Seishi Ogawa
  • Organizer: 2012 ASH Annual Meeting and Exposition
  • Place of Presentation: Atlanta, USA
  • Year and Date: 2012-12-08
• [Presentation] Genetic analysis of myelodneoplasms in childhood (2012)
  • Author(s): Seishi Ogawa
  • Organizer: Cambridge Research Institute Annual International Symposium
  • Place of Presentation: Cambridge, UK
  • Year and Date: 2012-11-02
• [Presentation] Deregulated RNA splicing Machinery in Myelodysplastic Syndromes (2012)
  • Author(s): Ogawa S.
  • Organizer: 2012 AACB meeting
  • Place of Presentation: Chicago, IL, USA(招待講演)
  • Year and Date: 2012-03-31
• [Presentation] Novel pathway mutations in myelodysplasia (2012)
  • Author(s): Ogawa S.
  • Organizer: Bone Marrow Failure Disease Scientific Symposium
  • Place of Presentation: Bethesda, ML, USA(招待講演)
  • Year and Date: 2012-03-22
• [Presentation] Genetic analysis of myelodysplastic syndromes and related disorders (2011)
  • Author(s): Ogawa S.
  • Organizer: US-JAPAN Cancer Workshop
  • Place of Presentation: Bethesda, ML, USA(招待講演)
  • Year and Date: 2011-10-25
• [Presentation] Genetic analysis of myelodysplastic syndromes and related disorders (2011)
  • Author(s): Ogawa S
  • Organizer: US-JAPAN CONFERENCE ON INFLAMM ATION, DIABETES AND CANCER
  • Place of Presentation: Duarte, CA, USA(招待講演)
  • Year and Date: 2011-08-05
• [Patent(Industrial Property Rights)] 骨髄異形成症候群または骨髄性腫瘍素因の評価方法, そのポリペプチド及び抗体 (2011)
  • Inventor(s): 小川誠司, 真田昌, 吉田健一
  • Industrial Property Rights Holder: 国立大学法人東京大学
  • Industrial Property Number: 2011-169662
  • Filing Date: 2011-08-02
• [Patent(Industrial Property Rights)] 骨髄異形成症候群または骨髄性腫瘍素因の評価方法、そのポリペプチド及び抗体 (2011)
  • Inventor(s): 小川誠司、真田昌、吉田健一
  • Industrial Property Rights Holder: 国立大学法人東京大学
  • Industrial Property Number: 2011-169662
  • Filing Date: 2011-08-02