Investigation of the pathogeneisis of myelodysplastic syndromes and its therapeutic biomarkers

• Project/Area Number: 15H05668
• Research Category: Grant-in-Aid for Young Scientists (A)
• Allocation Type: Single-year Grants
• Research Field: Hematology
• Research Institution: Kyoto University
• Principal Investigator: Yoshida Kenichi 京都大学, 医学研究科, 助教 (50738226)
• Project Period (FY): 2015-04-01 – 2017-03-31
• Project Status: Completed (Fiscal Year 2016)
• Budget Amount: ¥24,440,000 (Direct Cost: ¥18,800,000、Indirect Cost: ¥5,640,000); Fiscal Year 2016: ¥2,340,000 (Direct Cost: ¥1,800,000、Indirect Cost: ¥540,000); Fiscal Year 2015: ¥22,100,000 (Direct Cost: ¥17,000,000、Indirect Cost: ¥5,100,000)
• Keywords: 骨髄異形成症候群 / 癌 / ゲノム

Outline of Final Research Achievements

RNA sequencing of myelodysplastic syndromes revealed characteristic splicing abnormalities caused by mutations in RNA splicing factors, which were likely to be underlying mechanism of MDS pathogenesis. Gene expression analysis also separated MDS samples into two distinct groups, which were correlated with distinct prognosis. Whole-exome sequencing of serially collected MDS samples depicted complex pattern of clonal evolution in MDS patients with and without therapy. Targeted sequencing of MDS before and after treatment of demethylating agent, azacidine, revealed that most patient achieving complete remission harbored TP53 mutations, suggesting that TP53 mutations could be a therapeutic marker of azacitidine treatment.

Research Products

• [Int'l Joint Research] Radboud University(オランダ)
• [Int'l Joint Research] Cleaveland clinic(米国)
• [Int'l Joint Research] Cleaveland clinic(米国)
• [Journal Article] ynamics of clonal evolution in myelodysplastic syndromes. (2017)
  • Author(s): Makishima H, et al.
  • Journal Title: Nat Genet. Volume: 49 Issue: 2 Pages: 204-212
  • DOI: 10.1038/ng.3742
  • Peer Reviewed / Open Access / Int'l Joint Research / Acknowledgement Compliant
• [Journal Article] Clonal evolution in myelodysplastic syndromes. (2017)
  • Author(s): da Silva-Coelho P, Kroeze LI, Yoshida K, Koorenhof-Scheele TN, Knops R, van de Locht LT, de Graaf AO, Massop M, Sandmann S, Dugas M, Stevens-Kroef MJ, Cermak J, Shiraishi Y, Chiba K, Tanaka H, Miyano S, de Witte T, Blijlevens NMA, Muus P, Huls G, van der Reijden BA, Ogawa S, Jansen JH.
  • Journal Title: Nature Communications Volume: 印刷中 Issue: 1 Pages: 15099-15099
  • DOI: 10.1038/ncomms15099
  • NAID: 130005163316
  • Peer Reviewed / Open Access / Int'l Joint Research
• [Journal Article] Recurrent genetic defects on chromosome 5q in myeloid neoplasms. (2017)
  • Author(s): Hosono N, Makishima H, Mahfouz R, Przychodzen B, Yoshida K, Jerez A, LaFramboise T, Polprasert C, Clemente MJ, Shiraishi Y, Chiba K, Tanaka H, Miyano S, Sanada M, Cui E, Verma AK, McDevitt MA, List AF, Saunthararajah Y, Sekeres MA, Boultwood J, Ogawa S, Maciejewski JP.
  • Journal Title: Oncotarget. Volume: 8 Issue: 4 Pages: 6483-6495
  • DOI: 10.18632/oncotarget.14130
  • NAID: 120006355735
  • Peer Reviewed / Open Access / Int'l Joint Research / Acknowledgement Compliant
• [Journal Article] Impact of genetic alterations in stem-cell transplantation for myelodysplasia and secondary acute myeloid leukemia. (2017)
  • Author(s): Yoshizato T, et. al., Sanada M, et. al., Ogawa S.
  • Journal Title: Blood Volume: 129 Issue: 17 Pages: 2347-2358
  • DOI: 10.1182/blood-2016-12-754796
  • Peer Reviewed / Open Access / Int'l Joint Research / Acknowledgement Compliant
• [Journal Article] Somatic PHF6 mutations in 1760 cases with various myeloid neoplasms. (2016)
  • Author(s): Mori T, Nagata Y, Makishima H, Sanada M, Shiozawa Y, Kon A, Yoshizato T, Sato-Otsubo A, Kataoka K, Shiraishi Y, Chiba K, Tanaka H, Ishiyama K, Miyawaki S, Mori H, Nakamaki T, Kihara R, Kiyoi H, Koeffler HP, Shih LY, Miyano S, Naoe T, Haferlach C, Kern W, Haferlach T, Ogawa S, Yoshida K.
  • Journal Title: Leukemia. Volume: 30 Issue: 11 Pages: 2270-2273
  • DOI: 10.1038/leu.2016.212
  • Peer Reviewed / Open Access / Int'l Joint Research / Acknowledgement Compliant
• [Journal Article] BRCC3 mutations in myeloid neoplasms. (2015)
  • Author(s): Huang D, Nagata Y, Grossmann V, Radivoyevitch T, Okuno Y, Nagae G, et al.
  • Journal Title: Haematologica. Volume: 100(8) Pages: 1051-7
  • DOI: 10.3324/haematol.2014.111989
  • Peer Reviewed / Open Access / Int'l Joint Research
• [Journal Article] Inherited and Somatic Defects in DDX41 in Myeloid Neoplasms. (2015)
  • Author(s): Polprasert C, Schulze I, Sekeres MA, et. al. Ogawa S.
  • Journal Title: Cancer Cell. Volume: 27(5) Issue: 5 Pages: 658-70
  • DOI: 10.1016/j.ccell.2015.03.017
  • Peer Reviewed / Open Access / Int'l Joint Research
• [Presentation] Genetic Landscape and Clonal Evolution Following 5-Aza Therapy in Patients with High-Risk Myelodysplastic Syndromes (2016)
  • Author(s): June Takeda, Yusuke Shiozawa, Yuichi Shiraishi, Yusuke Okuno, Keisuke Kataoka, Kenichi Chiba, Hiroko Tanaka, Masashi Sanada, Shigeru Chiba, Norio Asou, Hitoshi Kiyoi, Yasushi Miyazaki, Hideki Makishima, Satoru Miyano, Seishi Ogawa, Kenichi Yoshida et al.
  • Organizer: 58th ASH Annual Meeting & Expositionnual meeting
  • Place of Presentation: San Diego
  • Int'l Joint Research
• [Presentation] Clonal evolution following azacitidine therapy in patients with high-risk my elodysplastic syndromes (2016)
  • Author(s): 竹田 淳恵、吉田 健一、牧島 秀樹、白石 友一、千葉 健一、千葉 滋、麻生 範雄、宮﨑 泰司、直江 知樹、清井 仁、宮野 悟、小川 誠司
  • Organizer: 第75回日本癌学会学術集会
  • Place of Presentation: 横浜
• [Presentation] Clonal evolution following azacitidine therapy in patients with high-risk myelodysplastic syndromes (2016)
  • Author(s): June Takeda, Kenichi Yoshida, Tetsuichi Yoshizato, Yusuke Shiozawa, Hideki Makishima, Yasuhito Nannya, Hiromichi Suzuki, Yuichi Shiraishi, Yusuke Okuno, Kenichi Chiba, Satoru Miyano, Masashi Sanada, Kensuke Usuki, Shigeru Chiba, Norio Asou, Yasuyuki Miyazaki, Tomoki Naoe, Hitoshi Kiyoi, Yukio Kobayashi, Seishi Ogawa
  • Organizer: 第78回日本血液学会学術集会
  • Place of Presentation: 横浜
• [Presentation] Clonal evolution underlying development of myelodysplastic syndromes (2015)
  • Author(s): Kenichi Yoshida
  • Organizer: 第77回日本血液学会学術集会
  • Place of Presentation: 金沢市アートホール
  • Year and Date: 2015-10-18
  • Invited