Analysis of autoimmune mechanisms of myelodysplastic syndromes

• Project/Area Number: 25670446
• Research Category: Grant-in-Aid for Challenging Exploratory Research
• Allocation Type: Single-year Grants
• Research Field: Hematology
• Research Institution: The University of Tokyo
• Principal Investigator: OGAWA Seishi 東京大学, 医学部附属病院, その他 (60292900)
• Project Period (FY): 2013-04-01 – 2014-03-31
• Project Status: Completed (Fiscal Year 2013)
• Budget Amount: ¥3,770,000 (Direct Cost: ¥2,900,000、Indirect Cost: ¥870,000); Fiscal Year 2013: ¥3,770,000 (Direct Cost: ¥2,900,000、Indirect Cost: ¥870,000)
• Keywords: 骨髄異形成症候群 / 自己免疫 / HLAテトラマー

Research Abstract

It was well known that many patients with aplastic anemia (AA) develop clonal disorders including myelodysplastic syndromes (MDS). Although the underlying mechanism is poorly understood, some escape from cytotoxic T-cells involved in AA pathogenesis is implicated in the progression to MDS. In this study, through a comprehensive analysis of somatic mutations in AA, we identified frequent somatic mutations of a wide variety of genes in as many as 60% of patients with AA. Some mutations affected known mutational targets in MDS, such as DNMT3A, ASXL1, and BCOR. Our results may indicated that these mutational targets could represent common targets of CTLs in AA, which when mutated, involved not only in escaping from CTL but also in clonal selection in MDS. It should be warranted in future studies to test whether these mutational targets encode common epitopes that are recognized by CTLs in AA.

Research Products

• [Journal Article] Somatic RHOA mutation in angioimmunoblastic T cell lymphoma. (2014)
  • Author(s): Sakata-Yanagimoto M, Yoshida K
  • Journal Title: Nature Genet. Volume: 46 Issue: 2 Pages: 171-175
  • DOI: 10.1038/ng.2872
  • Peer Reviewed
• [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 myelodysplasticsyndromes (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, H. P. Klein, H. U. Dugas, M. Aburatani, H. Kohlmann, A. Miyano, S. Haferlach, C. Kern, W. Ogawa, S.
  • Journal Title: Leukemia Volume: 28 Pages: 241-7
  • Peer Reviewed
• [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] 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] Integrated molecular analysis of clear-cell renal cell carcinoma. (2013)
  • Author(s): Sato Y, Yoshida K
  • Journal Title: Nature Genet. Volume: 45 Issue: 8 Pages: 860-867
  • DOI: 10.1038/ng.2699
  • 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
• [Presentation] Spectrum Of Genetic Alterations In Acquired Aplastic Anemia. (2013)
  • Author(s): 吉里哲一, 小川誠司 et al.
  • Organizer: 2013 ASH Annual Meeting and Exposition
  • Place of Presentation: NewOrleans, USA
  • Year and Date: 2013-12-08
• [Presentation] Spectrum of genetic alterations in acquired aplasticanemia. (2013)
  • Author(s): 吉里哲一, 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
  • Year and Date: 2013-10-13
• [Presentation] Spectrum of genetic alterations in acquired aplasticanemia (2013)
  • Author(s): 吉里哲一, 小川誠司 et al.
  • Organizer: 18th Congress of EHA
  • Place of Presentation: Stockholm, Sweden
  • Year and Date: 2013-06-16
• [Presentation] Spectrum of genetic alterations in acquired aplastic anemia (2013)
  • Author(s): 吉里哲一, 小川誠司 et al.,
  • Organizer: 18th Congress of EHA
  • Place of Presentation: Stockholm(Sweden)
• [Presentation] Spectrum of genetic alterations in acquired aplastic anemia (2013)
  • Author(s): 吉里哲一, 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
• [Presentation] Spectrum Of Genetic Alterations In Acquired Aplastic Anemia (2013)
  • Author(s): 吉里哲一, 小川誠司 et al.,
  • Organizer: 2013 ASH Annual Meeting and Exposition
  • Place of Presentation: New Orleans (USA)
• [Patent(Industrial Property Rights)] RHOA遺伝子及びその産物であるRHOA蛋白質の新規変異の発見と、疾患診断・治療への応用 (2013)
  • Inventor(s): 千葉滋, 坂田真実子, 小川誠司
  • Industrial Property Rights Holder: 国立大学法人東京大学
  • Industrial Property Rights Type: 特許
  • Filing Date: 2013-05-01
• [Patent(Industrial Property Rights)] RHOA遺伝子及びその産物であるRHOA蛋白質の新規変異の発見と、疾患診断・治療への応用 (2013)
  • Inventor(s): 千葉滋, 坂田真実子, 小川誠司
  • Industrial Property Rights Holder: 国立大学法人東京大学
  • Industrial Property Rights Type: 特許
  • Filing Date: 2013-05-01
  • Overseas