Molecular basis of MDS pathogenesis and construction of novel MDS prognostic model

• Project/Area Number: 21K08366
• Research Category: Grant-in-Aid for Scientific Research (C)
• Allocation Type: Multi-year Fund
• Section: 一般
• Review Section: Basic Section 54010:Hematology and medical oncology-related
• Research Institution: The University of Tokyo
• Principal Investigator: Oshima Motohiko 東京大学, 医科学研究所, 講師 (70506287)
• Project Period (FY): 2021-04-01 – 2024-03-31
• Project Status: Completed (Fiscal Year 2023)
• Budget Amount: ¥4,160,000 (Direct Cost: ¥3,200,000、Indirect Cost: ¥960,000); Fiscal Year 2023: ¥1,040,000 (Direct Cost: ¥800,000、Indirect Cost: ¥240,000); Fiscal Year 2022: ¥1,430,000 (Direct Cost: ¥1,100,000、Indirect Cost: ¥330,000); Fiscal Year 2021: ¥1,690,000 (Direct Cost: ¥1,300,000、Indirect Cost: ¥390,000)
• Keywords: MDS / ATAC-seq / 転写因子 / 造血器腫瘍 / 骨髄異形成症候群 / 造血幹細胞

Outline of Research at the Start

現行の骨髄異形成症候群 (MDS)の予後予測システムには不十分な部分があり、MDS病態の分子基盤に基づく新規予後因子を含む、新たな予後予測システムの構築が課題となっている。本研究では、MDS幹・前駆細胞を用いて、ATAC-seqによるクロマチン特性解析とRNA-seq、遺伝子変異解析を行い、分子プロファイルを用いた機械学習により、臨床情報や予後の予測を行う。予測に高い寄与度を示す新規予後因子を抽出し、 in vitro、 in vivo機能解析を行うことで、MDS病態の包括的な分子基盤の解明と、新規予後予測システムの構築を行う。

Outline of Final Research Achievements

ATAC-seq analysis of MDS using stem and progenitor fraction revealed that, differentially accessible regions (DARs) in MDS include large amount of normal differentiation-related regions. We also found the transcription factor networks that strongly related to the prognosis and stratified MDS based on the transcription factor network abnormality in MDS stem and progenitor cells. These characteristic features were not clearly observed in the gene expression profiles from same samples, showing that these finding are the first to be revealed by focusing on chromatin characteristics.

Academic Significance and Societal Importance of the Research Achievements

MDS幹細胞および前駆細胞分画を用いたクロマチン特性解析により、予後に関わる転写因子ネットワークを同定するとともに、転写因子ネットワーク変動に基づく新規のMDSサブグループが存在する事を明らかにした。今後、遺伝子変異との関わりや転写因子の標的遺伝子群などについてさらに詳細に検証を行うことで、新たなMDS病態の分子基盤を構築し、より適切な治療選択や新規治療法の開発に繋げる事が期待される。

Research Products

• [Journal Article] UTX inactivation in germinal center B cells promotes the development of multiple myeloma with extramedullary disease (2023)
  • Author(s): Rizq Ola、Mimura Naoya、Oshima Motohiko、Momose Shuji、Takayama Naoya、Itokawa Naoki、Koide Shuhei、Shibamiya Asuka、Miyamoto-Nagai Yurie、Rizk Mohamed、Nakajima-Takagi Yaeko、Aoyama Kazumasa、Wang Changshan、Saraya Atsunori、Ito Ryoji、Seimiya Masanori、et al
  • Journal Title: Leukemia Volume: 37 Issue: 9 Pages: 1895-1907
  • DOI: 10.1038/s41375-023-01928-7
  • Peer Reviewed / Open Access / Int'l Joint Research
• [Journal Article] Polycomb repressive complex 1.1 coordinates homeostatic and emergency myelopoiesis (2023)
  • Author(s): Nakajima-Takagi Yaeko、Oshima Motohiko、Takano Junichiro、Koide Shuhei、Itokawa Naoki、Uemura Shun、Yamashita Masayuki、Andoh Shohei、Aoyama Kazumasa、Isshiki Yusuke、Shinoda Daisuke、Saraya Atsunori、Arai Fumio、Yamaguchi Kiyoshi、Furukawa Yoichi、Koseki Haruhiko、Ikawa Tomokatsu、Iwama Atsushi
  • Journal Title: eLife Volume: 12
  • DOI: 10.7554/elife.83004
  • Peer Reviewed / Open Access
• [Journal Article] Unraveling unique features of plasma cell clones in POEMS syndrome with single-cell analysis. (2022)
  • Author(s): Isshiki Y, Oshima M, Mimura N, Kayamori K, Miyamoto-Nagai Y, Seki M, Nakajima-Takagi Y, Kanamori T, Iwamoto E, Muto T, Tsukamoto S, Takeda Y, Ohwada C, Misawa S, Ikeda JI, Sanada M, Kuwabara S, Suzuki Y, Sakaida E, Nakaseko C, Iwama A.
  • Journal Title: JCI Insight Volume: 7 Issue: 20 Pages: 1-13
  • DOI: 10.1172/jci.insight.151482
  • Peer Reviewed / Open Access / Int'l Joint Research
• [Journal Article] YAP1/TAZ activity maintains vascular integrity and organismal survival (2022)
  • Author(s): Uemura Shun、Yamashita Masayuki、Aoyama Kazumasa、Yokomizo-Nakano Takako、Oshima Motohiko、Nishio Miki、Masuko Masayoshi、Takizawa Jun、Sone Hirohito、Yamada Yasuhiro、Suzuki Akira、Iwama Atsushi
  • Journal Title: Biochemical and Biophysical Research Communications Volume: 619 Pages: 117-123
  • DOI: 10.1016/j.bbrc.2022.06.050
  • Peer Reviewed / Open Access
• [Journal Article] Epigenetic Memories in Hematopoietic Stem and Progenitor Cells (2022)
  • Author(s): Aoyama Kazumasa、Itokawa Naoki、Oshima Motohiko、Iwama Atsushi
  • Journal Title: Cells Volume: 11 Issue: 14 Pages: 2187-2187
  • DOI: 10.3390/cells11142187
  • Peer Reviewed / Open Access
• [Journal Article] Epigenetic traits inscribed in chromatin accessibility in aged hematopoietic stem cells (2022)
  • Author(s): Itokawa Naoki、Oshima Motohiko、Koide Shuhei、Takayama Naoya、Kuribayashi Wakako、Nakajima-Takagi Yaeko、Aoyama Kazumasa、Yamazaki Satoshi、Yamaguchi Kiyoshi、Furukawa Yoichi、Eto Koji、Iwama Atsushi
  • Journal Title: Nature Communications Volume: 13 Issue: 1 Pages: 2691-2691
  • DOI: 10.1038/s41467-022-30440-2
  • Peer Reviewed / Open Access / Int'l Joint Research
• [Journal Article] DHODH inhibition synergizes with DNA-demethylating agents in the treatment of myelodysplastic syndromes (2021)
  • Author(s): Kayamori Kensuke、Nagai Yurie、Zhong Cheng、Kuribayashi Wakako、Oshima Motohiko、Nakajima-Takagi Yaeko、Yamashita Masayuki、Mimura Naoya、Becker Hans Jiro、Izawa Kiyoko、Yamazaki Satoshi、Iwano Satoshi、Ito Ryoji、Lennox William、Sheedy Josephine、Yokote Koutaro、Iwama Atsushi
  • Journal Title: Blood Advances Volume: 5 Issue: 2 Pages: 438-450
  • DOI: 10.1182/bloodadvances.2020001461
  • Peer Reviewed / Open Access / Int'l Joint Research
• [Journal Article] Limited rejuvenation of aged hematopoietic stem cells in young bone marrow niche (2021)
  • Author(s): Kuribayashi W, Oshima M, Itokawa N, Koide S, Nakajima-Takagi Y, Yamashita M, Yamazaki S, Rahmutulla B, Miura F, Ito T, Kaneda A, Iwama A.
  • Journal Title: J Exp Med Volume: 218 Issue: 3
  • DOI: 10.1084/jem.20192283
  • Peer Reviewed / Open Access / Int'l Joint Research
• [Journal Article] Insufficiency of non-canonical PRC1 synergizes with JAK2V617F in the development of myelofibrosis (2021)
  • Author(s): Shinoda Daisuke、Nakajima-Takagi Yaeko、Oshima Motohiko、Koide Shuhei、Aoyama Kazumasa、Saraya Atsunori、Harada Hironori、Rahmutulla Bahityar、Kaneda Atsushi、Yamaguchi Kiyoshi、Furukawa Yoichi、Koseki Haruhiko、Shimoda Kazuya、Tanaka Tomoaki、Sashida Goro、Iwama Atsushi
  • Journal Title: Leukemia Volume: 36 Issue: 2 Pages: 452-463
  • DOI: 10.1038/s41375-021-01402-2
  • Peer Reviewed / Open Access
• [Journal Article] PRC2 insufficiency causes p53-dependent dyserythropoiesis in myelodysplastic syndrome (2020)
  • Author(s): Aoyama K, Shinoda D, Suzuki E, Nakajima-Takagi Y, Oshima M, Koide S, Rizq O, Si S, Tara S, Sashida G, Iwama A.
  • Journal Title: Leukemia Volume: 4 Issue: 4 Pages: 1156-1165
  • DOI: 10.1038/s41375-020-01023-1
  • Peer Reviewed / Open Access / Int'l Joint Research
• [Presentation] Chromatin accessibility in stem cells unveils progressive transcriptional reprogramming in MDS (2023)
  • Author(s): Oshima M, Takayama N, Nakajima-Takagi Y, Koide S, Harada H, Harada Y, Ding Y, Myojo T, Iwama A.
  • Organizer: 第85回日本血液学会学術集会
  • Int'l Joint Research
• [Presentation] クロマチン特性解析による骨髄異形成症候群の病態解明 (2023)
  • Author(s): 大島基彦, 高山直也, 中島やえ子, 小出周平, 原田浩徳, 原田結花, 岩間厚志
  • Organizer: 第27回造血器腫瘍研究会
• [Presentation] Molecular pathogenesis in MDS stem and progenitor cells (2022)
  • Author(s): Oshima M, Takayama N, Nakajima-Takagi Y, Koide S, Harada H, Harada Y, Ding Y, Myojo T, Iwama A.
  • Organizer: 第83回日本血液学会学術集会
• [Presentation] MDS病態の分子基盤の解明と新規予後予測システムの構築 (2021)
  • Author(s): 大島基彦，高山直也，中島やえ子，小出周平，岩間厚志.
  • Organizer: 第２５回造血器腫瘍研究会