Clonal architecture of myeloid malignancies as revealed by single-cell RNA sequencing.

• Project/Area Number: 17K19595
• Research Category: Grant-in-Aid for Challenging Research (Exploratory)
• Allocation Type: Multi-year Fund
• Research Field: Tumor biology and related fields
• Research Institution: Kyoto University
• Principal Investigator: OGAWA SEISHI 京都大学, 医学研究科, 教授 (60292900)
• Research Collaborator: Takaori Akiumi ; Miyano Satoru ; Nakagawa Masahiro
• Project Period (FY): 2017-06-30 – 2019-03-31
• Project Status: Completed (Fiscal Year 2018)
• Budget Amount: ¥6,500,000 (Direct Cost: ¥5,000,000、Indirect Cost: ¥1,500,000); Fiscal Year 2018: ¥3,250,000 (Direct Cost: ¥2,500,000、Indirect Cost: ¥750,000); Fiscal Year 2017: ¥3,250,000 (Direct Cost: ¥2,500,000、Indirect Cost: ¥750,000)
• Keywords: 骨髄異形成症候群 / 白血病 / クローン進展 / 単一細胞解析 / 腫瘍内多様性

Outline of Final Research Achievements

The development and progression of acute myeloid leukemia (AML) are shaped by multiple rounds of acquisition of new driver mutations and subsequent clonal selection. These clonal evolutions develop substantial intra-tumor heterogeneity, which is one of the major reasons of treatment failure and relapse.
Recent development of single-cell analysis method has provided a novel opportunity to understand this complexity, which however, is severely hampered by the difficulty to detect both mutations and expression profiles at the same time. To overcome this, we developed a robust method for simultaneous detection of both mutations and gene expression in this study.

Academic Significance and Societal Importance of the Research Achievements

近年、一見正常に見える組織においても、加齢や生活習慣によりドライバー変異を有するクローンの拡大が見られることが、我々や他のグループによって明らかになっている。これらのクローン拡大は、がんの初期発生に重要と考えられるが、その詳細な機構は未だ明らかでない。本研究で開発した手法は、さらなる最適化により、様々な組織におけるこのようなクローン拡大の解析に利用可能であり、がんの初期発生の理解の進展に大きく寄与することが期待される。

Research Products

• [Journal Article] Age-related remodelling of oesophageal epithelia by mutated cancer drivers. (2019)
  • Author(s): Yokoyama A, Ogawa S., et al.
  • Journal Title: Nature Volume: 565 Issue: 7739 Pages: 312-317
  • DOI: 10.1038/s41586-018-0811-x
  • Peer Reviewed / Open Access / Int'l Joint Research
• [Journal Article] Molecular pathogenesis of disease progression in MLL-rearranged AML. (2018)
  • Author(s): Kotani S, Yoda A, Kon A, Kataoka K, Ochi Y, Shiozawa Y, Hirsch C, Takeda J, Ueno H, Yoshizato T, Yoshida K, Nakagawa MM, Nannya Y, Kakiuchi N, Yamauchi T, Aoki K, Shiraishi Y, Miyano S, Maeda T, Maciejewski JP, Takaori-Kondo A, Ogawa S, Makishima H.
  • Journal Title: Leukemia Volume: 33 Issue: 3 Pages: 612-624
  • DOI: 10.1038/s41375-018-0253-3
  • Peer Reviewed / Open Access / Int'l Joint Research
• [Presentation] Mechanisms of the clonal evolution of MDS as revealed by single-cell sequencing. (2018)
  • Author(s): Masahiro M Nakagawa, Ryosaku Inagaki, Yasuhito Nannya, Zhao Lanying, June Takeda, Akinori Yoda, Ayana Kon, Tetsuichi Yoshizato, Hideki Makishima, and Seishi Ogawa
  • Organizer: 第77回日本癌学会学術総会
• [Presentation] Development of a single-cell sequencing platform enabling simultaneous detection of both gene mutation and expression (2018)
  • Author(s): Ryosaku Inagaki, Masahiro M Nakagawa, Yasuhito Nannya, Keisuke Kataoka, Tetsuichi Yoshizato, Hideki Makishima, Kenichi Yoshida, Seishi Ogawa
  • Organizer: 第77回日本癌学会学術総会
• [Presentation] Mechanisms of the clonal evolution of MDS as revealed by single-cell sequencing. (2018)
  • Author(s): Masahiro M Nakagawa, Ryosaku Inagaki, Yasuhito Nannya, Zhao Lanying, June Takeda, Akinori Yoda, Ayana Kon, Tetsuichi Yoshizato, Hisashi Tsurumi, Hideki Makishima, and Seishi Ogawa
  • Organizer: 第80回日本血液学会学術総会
• [Presentation] Development of a single-cell sequencing platform enabling detection of both mutation and expression (2018)
  • Author(s): Masahiro M Nakagawa, Ryosaku Inagaki, Yasuhito Nannya, Zhao Lanying, June Takeda, Akinori Yoda, Ayana Kon, Tetsuichi Yoshizato, Hisashi Tsurumi, Hideki Makishima, and Seishi Ogawa
  • Organizer: 第80回日本血液学会学術総会
• [Presentation] Analysis of clonal evolution/heterogeneity of MDS by simultaneous detection of both mutation and gene expression by single cell sequencing (2018)
  • Author(s): Masahiro Marshall Nakagawa, Ryosaku Inagaki, Yasuhito Nannya, Lanying Zhao, Yutaka Kuroda, June Takeda, Xingxing Qi, Akinori Yoda, Ayana Kon, Hisashi Tsurumi, Hideki Makishima, Shuichi Matsuda and Seishi Ogawa
  • Organizer: 60th ASH Annual Meeting
  • Int'l Joint Research
• [Presentation] Development of a method for high-throughput single-cell RNA sequencing with mutation information (2017)
  • Author(s): Ryosaku Inagaki, Masahiro M Nakagawa, Yasuhito Nannya, Keisuke Kataoka, Tetsuichi Yoshizato, Hideki Makishima, Kenichi Yoshida, Seishi Ogawa
  • Organizer: 第76回日本癌学会学術総会
• [Presentation] Mechanisms of the clonal evolution of myeloid malignancies as revealed by single-cell sequencing. (2017)
  • Author(s): Masahiro M Nakagawa, Ryosaku Inagaki, Yasuhito Nannya, Keisuke Kataoka, Tetsuichi Yoshizato, Hideki Makishima, Kenichi Yoshida, and Seishi Ogawa
  • Organizer: 第76回日本癌学会学術総会
• [Presentation] Mechanisms of the clonal evolution of MDS as revealed by single-cell sequencing. (2017)
  • Author(s): Masahiro M Nakagawa, Ryosaku Inagaki, Yasuhito Nannya, Keisuke Kataoka, Tetsuichi Yoshizato, Hideki Makishima, Kenichi Yoshida, and Seishi Ogawa
  • Organizer: 第79回日本血液学会学術集会