Study of pathogenic mechanism of age-dependent chromosome translocation in adult acute lymphoblastic leukemia

• Project/Area Number: 18K16103
• Research Category: Grant-in-Aid for Early-Career Scientists
• Allocation Type: Multi-year Fund
• Review Section: Basic Section 54010:Hematology and medical oncology-related
• Research Institution: National Hospital Organization Nagoya Medical Center
• Principal Investigator: Yasuda Takahiko 独立行政法人国立病院機構(名古屋医療センター臨床研究センター), その他部局等, 分子診断研究室長 (20723977)
• Project Period (FY): 2018-04-01 – 2020-03-31
• Project Status: Completed (Fiscal Year 2019)
• Budget Amount: ¥4,160,000 (Direct Cost: ¥3,200,000、Indirect Cost: ¥960,000); Fiscal Year 2019: ¥1,820,000 (Direct Cost: ¥1,400,000、Indirect Cost: ¥420,000); Fiscal Year 2018: ¥2,340,000 (Direct Cost: ¥1,800,000、Indirect Cost: ¥540,000)
• Keywords: 融合遺伝子 / 年齢依存的 / 急性リンパ性白血病 / AYA / RNA-seq / breakpoint / 染色体転座 / RAG / AID

Outline of Final Research Achievements

In Acute Lymphoblastic Leukemia (ALL), fusion genes play a major role in tumor development. It is known that the type of fusion gene and its frequency fluctuate in an age-dependent manner. For example, ETV6-RUNX1 frequently occurs in childhood and BCR-ABL1 frequently occurs in adults. We performed RNA sequencing using samples from both the ALL202-U and ALL202-O cohorts conducted by JALSG (Japan Adult Leukemia study Group) to detect fusion genes comprehensively. As a result, we clarified the type and frequency of fusion genes in Japanese adults, and also revealed the relationship between onset age and fusion genes.

Academic Significance and Societal Importance of the Research Achievements

融合遺伝子とその年齢の関連性を解析したところ、DUX4 融合遺伝子とMEF2D 融合遺伝子はAYA世代（15-39歳）で好発する一方、Ph-like ALL（キナーゼ関連融合遺伝子）とZNF384融合遺伝子はAYAと成人（40-64歳）の両世代に均等に発症することが明らかとなった。これらの融合遺伝子がなぜ年齢依存性を示すか、ゲノム上の融合点の特徴から解明を目指した。DUX4融合遺伝子の融合点付近には、RAGが認識するコンセンサス配列が確認されたが、それ以外の他の融合遺伝子には特徴的な配列は確認されなかった。年齢依存的に融合遺伝子が発症するメカニズムの解明に向けて、更なるアプローチが必要である。

Research Products

• [Journal Article] Genomic analysis of multiple myeloma using targeted capture sequencing in the Japanese cohort. (2020)
  • Author(s): Kanamori T, Sanada M, Ri M, Ueno H, Nishijima D, Yasuda T, Tachita T, Narita T, Kusumoto S, Inagaki A, Ishihara R, Murakami Y, Kobayashi N, Shiozawa Y, Yoshida K, Nakagawa MM, Nannya Y, Shiraishi Y, Chiba K, Tanaka H, Miyano S, Horibe K, Handa H, Ogawa S, Iida S.
  • Journal Title: Br J Haematol. Volume: - Issue: 5 Pages: 755-763
  • DOI: 10.1111/bjh.16720
  • Peer Reviewed / Open Access / Int'l Joint Research
• [Journal Article] ZNF384-fusion proteins have high affinity for the transcriptional coactivator EP300 and aberrant transcriptional activities. (2019)
  • Author(s): 3.Yamamoto H, Hayakawa F, Yasuda T, Odaira K, Minamikawa Y, Tange N, Hirano D,Kojima Y, Morishita T, Tsuzuki S, Naoe T, Kiyoi H.
  • Journal Title: FEBS Lett. Volume: 593 Issue: 16 Pages: 2151-2161
  • DOI: 10.1002/1873-3468.13506
  • Peer Reviewed / Open Access
• [Journal Article] Precision medicine in hematological malignancies (2019)
  • Author(s): 安田 貴彦、堀部 敬三
  • Journal Title: Rinsho Ketsueki Volume: 60 Issue: 9 Pages: 1386-1395
  • DOI: 10.11406/rinketsu.60.1386
  • NAID: 130007724644
  • ISSN: 0485-1439, 1882-0824
  • Peer Reviewed
• [Journal Article] Chromosomal translocation-mediated evasion from miRNA induces strong MEF2D fusion protein expression, causing inhibition of PAX5 transcriptional activity. (2019)
  • Author(s): Hirano D, Hayakawa F, Yasuda T, Tange N, Yamamoto H, Kojima Y, Morishita T, Imoto N, Tsuzuki S, Mano H, Naoe T, Kiyoi H.
  • Journal Title: Oncogene Volume: 38 Issue: 13 Pages: 2263-2274
  • DOI: 10.1038/s41388-018-0573-9
  • Peer Reviewed
• [Journal Article] Transcriptional landscape of B cell precursor acute lymphoblastic leukemia based on an international study of 1,223 cases. (2018)
  • Author(s): Li JF, Dai YT, Kubota Y, Kiyoi H, Matsumura I, Miyazaki Y, Olsson L, Tan AM, Ariffin H, Chen J, Takita J, Yasuda T, Mano H, Johansson B, Yang JJ, Yeoh AE, Hayakawa F, Chen Z, Pui CH, Fioretos T, Chen SJ, Huang JY.
  • Journal Title: Proc Natl Acad Sci U S A Volume: 115 Issue: 50
  • DOI: 10.1073/pnas.1814397115
  • Peer Reviewed / Open Access / Int'l Joint Research
• [Journal Article] Transcriptional activities of DUX4 fusions in B-cell acute lymphoblastic leukemia (2018)
  • Author(s): Tanaka Yosuke、Kawazu Masahito、Yasuda Takahiko、Tamura Miki、Hayakawa Fumihiko、Kojima Shinya、Ueno Toshihide、Kiyoi Hitoshi、Naoe Tomoki、Mano Hiroyuki
  • Journal Title: Haematologica Volume: 103 Issue: 11 Pages: 522-526
  • DOI: 10.3324/haematol.2017.183152
  • Peer Reviewed / Open Access
• [Presentation] 造血器腫瘍におけるプレシジョン・メディシン (2019)
  • Author(s): 安田貴彦
  • Organizer: 第81回日本血液学会学術集会
  • Invited
• [Presentation] がん領域におけるクリニカルシーケンスのための臨床ゲノム情報データベースの開発 (2019)
  • Author(s): 齋藤 俊樹, 濱野 康司, 山本 松雄, 安田 貴彦, 真田 昌, 永井 宏和, 堀部 敬三
  • Organizer: 第81回日本血液学会学術集会
• [Presentation] がん領域におけるクリニカルシーケンスのための臨床ゲノム情報デー タベースの開発 (2019)
  • Author(s): 齋藤 俊樹、安田 貴彦、真田 昌、永井 宏和、堀部 敬三
  • Organizer: 第78回日本癌学会学術総会
• [Presentation] Novel Molecular pathogenesis and therapeutic target in acute erythroid leukemia. (2019)
  • Author(s): Takashi Kanamori, Masashi Sanada, Dai Nishijima, Takahiko Yasuda
  • Organizer: Congress of the European Hematology Association (EHA24)
  • Int'l Joint Research
• [Presentation] Genomic and Clinical Characterization of Adult Ph-Negative B-Cell Acute Lymphoblastic Leukemia (2018)
  • Author(s): Takahiko Yasuda, Dai Nishijima, Shinya Kojima, Masahito Kawazu, Toshihide Ueno, Shinobu Tsuzuki, Hitoshi Kiyoi, Itaru Matsumura, Yasushi Miyazaki, Keizo Horibe, Hiroyuki Mano, Tomoki Naoe, Masashi Sanada, Fumihiko Hayakawa
  • Organizer: 60th ASH Annual Meeting & Exposition
  • Int'l Joint Research
• [Presentation] 成人B細胞性急性リンパ性白血病のゲノム学的・臨床的な特徴 (2018)
  • Author(s): 安田 貴彦, 西島 大, 小島 進也, 河津 正人, 上野 敏秀, 都築 忍, 清井 仁, 松村 到, 宮崎 泰司, 堀部 敬三, 間野 博行, 直江 知樹, 眞田 昌, 早川 文彦
  • Organizer: 第80回日本血液学会学術集会
• [Presentation] ZNF384-Fusion Proteins Have High Affinity to EP300, Which Increases Their Transcriptional Activities. (2018)
  • Author(s): Hideyuki Yamamoto, Fumihiko Hayakawa, Takahiko Yasuda, Yuka Minamikawa, Naoyuki Tange, Daiki Hirano, Yuki Kojima, Takanobu Morishita, Shinobu Tsuzuki, Hiroyuki Mano, Tomoki Naoe and Hitoshi Kiyoi
  • Organizer: 60th ASH Annual Meeting & Exposition
  • Int'l Joint Research
• [Presentation] ZNF384融合遺伝子による急性リンパ性白血病発症機構の解明 (2018)
  • Author(s): 山本 秀行, 早川 文彦, 安田 貴彦, 南川 友香, 丹下 直幸, 平野 大希, 小島 勇貴, 森下 喬允, 都築 忍, 間野 博行, 直江 知樹, 清井 仁
  • Organizer: 第80回日本血液学会学術集会
• [Presentation] DUX4-IGH融合遺伝子陽性B細胞急性リンパ性白血病における転写活性解析 (2018)
  • Author(s): 田中 庸介, 河津 正人, 安田 貴彦, 早川 文彦, 清井 仁, 直江 知樹, 間野 博行
  • Organizer: 第80回日本血液学会学術集会