Investigation of molecular mechanism of new recurrent fusion genes in ALL

• Project/Area Number: 18H02835
• Research Category: Grant-in-Aid for Scientific Research (B)
• Allocation Type: Single-year Grants
• Section: 一般
• Review Section: Basic Section 54010:Hematology and medical oncology-related
• Research Institution: Nagoya University
• Principal Investigator: Hayakawa Fumihiko 名古屋大学, 医学系研究科(保健), 教授 (30402580)
• Project Period (FY): 2018-04-01 – 2021-03-31
• Project Status: Completed (Fiscal Year 2020)
• Budget Amount: ¥16,510,000 (Direct Cost: ¥12,700,000、Indirect Cost: ¥3,810,000); Fiscal Year 2020: ¥4,680,000 (Direct Cost: ¥3,600,000、Indirect Cost: ¥1,080,000); Fiscal Year 2019: ¥5,460,000 (Direct Cost: ¥4,200,000、Indirect Cost: ¥1,260,000); Fiscal Year 2018: ¥6,370,000 (Direct Cost: ¥4,900,000、Indirect Cost: ¥1,470,000)
• Keywords: 急性リンパ性白血病 / MEF2D / ZNF384 / 薬剤スクリーニング / マイクロRNA / スタウロスポリン / カスペース / 融合遺伝子 / 発がんメカニズム / SALL4 / ID2 / micro RNA / 白血病 / 遺伝子解析

Outline of Final Research Achievements

In the present study, we clarified molecular mechanisms of leukemia development by MEF2D-fusion gene and ZNF384-fusion gene, new recurrent gene abnormalities of acute lymphoblastic leukemia. MEF2D fusion gene evaded from the inhibition by miRNA, which caused higher expression of MEF2D fusion protein than wild-type MEF2D. Highly expressed MEF2D fusion protein inhibited the transcriptional activity of PAX5. We also revealed that ZNF384 fusion protein had stronger binding affinity to co-activator such as EP300 than wild-type, which lead to its stronger transcriptional activity. Furthermore, we performed drug screening to discover compounds that cause proteolysis of MEF2D-fusion protein. We found that staurosporine, a multi-kinase inhibitor, was a such drug and caused apoptosis of MEF2D-fusion gene positive ALL cell lines.

Academic Significance and Societal Importance of the Research Achievements

MEF2D融合遺伝子、ZNF384融合遺伝子は最近発見され、白血病化機序など全く不明の遺伝子異常であるが、それぞれ、日本人成人急性リンパ性白血病の10%、20%程度を占める高頻度遺伝子異常である。このような白血病に関して、将来の治療薬開発のための標的となる分子が明らかにされたり、既存の化合物の中から治療薬となりうる化合物をスクリーニングする手法が開発されたことの意義は大きいと考えられる。

Research Products

• [Int'l Joint Research] Shanghai Jiao Tong University(中国)
• [Int'l Joint Research] St. Jude Children’s Research Hospital(米国)
• [Int'l Joint Research] Lund University(スウェーデン)
• [Int'l Joint Research] University of Malaya Medical Centre(マレーシア)
• [Int'l Joint Research] Yong Loo Lin School of Medicine(シンガポール)
• [Journal Article] Essential role of a carboxyl-terminal α-helix motif in the secretion of coagulation factor XI. (2021)
  • Author(s): Hayakawa Y, Tamura S, Suzuki N, Odaira K, Tokoro M, Kawashima F, Hayakawa F, Takagi A, Katsumi A, Suzuki A, Okamoto S, Kanematsu T, Matsushita T, Kojima T.
  • Journal Title: Journal of Thrombosis and Haemostasis Volume: - Pages: 920-930
  • DOI: 10.1111/jth.15242
  • Peer Reviewed / Open Access
• [Journal Article] Combination of clofarabine, etoposide, and cyclophosphamide in adult relapsed/refractory acute lymphoblastic leukemia: a phase 1/2 dose-escalation study by the Japan Adult Leukemia Study Group. (2021)
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  • Journal Title: Int J Hematol. Volume: 113 Pages: 395-403
  • DOI: 10.1007/s12185-020-03032-3
  • Peer Reviewed / Open Access
• [Journal Article] JSH practical guidelines for hematological malignancies, 2018: I. leukemia-3. acute lymphoblastic leukemia/lymphoblastic lymphoma (ALL/LBL). (2020)
  • Author(s): Hatta Y, Hayakawa F, Yamazaki E.
  • Journal Title: Int J Hematol. Volume: 112 Pages: 439-458
  • DOI: 10.1007/s12185-020-02965-z
  • Peer Reviewed
• [Journal Article] Functional analysis of a novel fusion protein PAX5-KIDINS220 identified in a pediatric Ph-like ALL patient. (2020)
  • Author(s): Kanayama T, Imamura T, Mayumi A, Soma E, Sakamoto K, Hayakawa F, Tanizawa A, Kiyokawa N, Hosoi H.
  • Journal Title: Int J Hematol. Volume: 112 Pages: 714-719
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• [Journal Article] A case of pemphigus with anti-desmoglein 3 and anti-desmocollin 2 and 3 autoantibodies, associated with follicular lymphoma and bronchiolitis obliterans. (2020)
  • Author(s): Yoshikawa M, Takeichi T, Taki T, Hayakawa F, Ishii N, Hashimoto T, Muro Y, Akiyama M.
  • Journal Title: Eur J Dermatol Volume: 30 Pages: 424-425
  • DOI: 10.1684/ejd.2020.3812
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• [Journal Article] Aberrant X chromosomal rearrangement through multi‐step template switching during sister chromatid formation in a patient with severe hemophilia A (2020)
  • Author(s): Tokoro Mahiru、Tamura Shogo、Suzuki Nobuaki、Kakihara Misaki、Hattori Yuna、Odaira Koya、Suzuki Sachiko、Takagi Akira、Katsumi Akira、Hayakawa Fumihiko、Okamoto Shuichi、Suzuki Atsuo、Kanematsu Takeshi、Matsushita Tadashi、Kojima Tetsuhito
  • Journal Title: Molecular Genetics and Genomic Medicine Volume: 8 Pages: 1-12
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  • Peer Reviewed / Open Access
• [Journal Article] Vaticanol C, a phytoalexin, induces apoptosis of leukemia and cancer cells by modulating expression of multiple sphingolipid metabolic enzymes (2020)
  • Author(s): Inoue C, Sobue S, Mizutani N, Kawamoto Y, Nishizawa Y, Ichihara M, Takeuchi T, Hayakawa F, Suzuki M, Ito T, Nozawa Y, Murate T.
  • Journal Title: Nagoya Journal of Medical Science Volume: 82 Issue: 2 Pages: 261-280
  • DOI: 10.18999/nagjms.82.2.261
  • NAID: 120006847437
  • ISSN: 2186-3326
  • URL: https://nagoya.repo.nii.ac.jp/records/30090
  • Peer Reviewed
• [Journal Article] High prevalence of MEF2D fusion in human B-cell precursor acute lymphoblastic leukemia cell lines. (2020)
  • Author(s): Akahane K, Yasuda T, Tsuzuki S, Hayakawa F, Kiyokawa N, Somazu S, Watanabe A, Kagami K, Abe M, Harama D, Goi K, Kawazu M, Kojima S, Imamura T, Goto H, Iwamoto S, Minegishi M, Abe M, Hojo H, Inaba T, Mano H, Sugita K, Inukai T.
  • Journal Title: Hematol Oncol Volume: 38 Pages: 614-617
  • DOI: 10.1002/hon.2762
  • Peer Reviewed / Open Access
• [Journal Article] Targeting MEF2D-fusion oncogenic transcriptional circuitries in B-cell precursor acute lymphoblastic leukemia (2020)
  • Author(s): Tsuzuki S, Yasuda T, Kojima S, Kawazu M, Akahane K, Inukai T, Imaizumi M, Morishita T, Miyamura K, Ueno T, Karnan S, Ota A, Hyodo T, Konishi H, Sanada M, Nagai H, Horibe K, Tomita A, Suzuki K, Muramatsu H, Takahashi Y, Miyazaki Y, Matsumura I, Kiyoi H, Hosokawa Y, Mano H, Hayakawa F.
  • Journal Title: Blood Cancer Discovery. Volume: 1 Pages: 82-95
  • Peer Reviewed / Open Access
• [Journal Article] Staurosporine and venetoclax induce the caspase-dependent proteolysis of MEF2D-fusion proteins and apoptosis in MEF2D-fusion (+) ALL cells. (2020)
  • Author(s): Tange N, Hayakawa F, Yasuda T, Odaira K, Yamamoto H, Hirano D, Sakai T, Terakura S, Tsuzuki S, Kiyoi H.
  • Journal Title: Biomed Pharmacother. Volume: 128 Pages: 110330-110330
  • DOI: 10.1016/j.biopha.2020.110330
  • Peer Reviewed / Open Access
• [Journal Article] Involvement of MCL1, c-myc, and cyclin D2 protein degradation in ponatinib-induced cytotoxicity against T315I(+) Ph+leukemia cells (2020)
  • Author(s): Inoue Chisato、Sobue Sayaka、Kawamoto Yoshiyuki、Nishizawa Yuji、Ichihara Masatoshi、Abe Akihiro、Hayakawa Fumihiko、Suzuki Motoshi、Nozawa Yoshinori、Murate Takahsi
  • Journal Title: Biochem Biophys Res Commun. Volume: 525 Pages: 1074-1080
  • DOI: 10.1016/j.bbrc.2020.02.165
  • Peer Reviewed
• [Journal Article] Higher FVIII:C Measured by Chromogenic Substrate Assay Than by One-Stage Assay Is Associated With Silent Hemophilic Arthropathy (2020)
  • Author(s): Mika Ogawa, Nobuaki Suzuki, Nobunori Takahashi, Shogo Tamura, Atsuo Suzuki, Sachiko Suzuki, Yuua Hattori, Misaki Kakihara, Takeshi Kanematsu, Toshihisa Kojima, Akira Katsumi, Fumihiko Hayakawa, Tetsuhito Kojima, Naoki Ishiguro , Hitoshi Kiyoi , Tadashi Matsushita
  • Journal Title: Thromb Res. Volume: 188 Pages: 103-105
  • DOI: 10.1016/j.thromres.2020.01.003
  • NAID: 120006872431
  • Peer Reviewed / Open Access
• [Journal Article] 【急性白血病-最新の診断と治療-】急性白血病の分子病態 AYA世代急性白血病の分子病態. (2020)
  • Author(s): 早川 文彦
  • Journal Title: 日本臨床 Volume: 78 Pages: 418-423
• [Journal Article] 最近の血栓止血異常のとらえかた 検査室や研究室から 先天性凝固異常症の遺伝子解析 解析のStrategyとPitfall. (2020)
  • Author(s): 田村 彰吾, 高木 明, 早川 文彦, 小嶋 哲人
  • Journal Title: 日本検査血液学会雑誌 Volume: 21 Pages: 71-78
• [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 Letters Volume: 593 Pages: 2151-2161
  • DOI: 10.1002/1873-3468.13506
  • Peer Reviewed / Open Access
• [Journal Article] Apparent Synonymous Mutation F9 c.87A>G Causes Secretion Failure by In-Frame Mutation With Aberrant Splicing (2019)
  • Author(s): Odaira K, Tamura S, Suzuki N, Kakihara M, Hattori Y, Tokoro M, Suzuki S, Takagi A, Katsumi A, Hayakawa F, Okamoto S, Suzuki A, Kanematsu T, Matsushita T, Kojima T.
  • Journal Title: Thrombosis Research Volume: 179 Pages: 95-103
  • DOI: 10.1016/j.thromres.2019.04.022
  • Peer Reviewed / Open Access
• [Journal Article] Molecular basis of SERPINC1 mutations in Japanese patients with antithrombin deficiency (2019)
  • Author(s): Tamura Shogo、Hashimoto Erika、Suzuki Nobuaki、Kakihara Misaki、Odaira Koya、Hattori Yuna、Tokoro Mahiru、Suzuki Sachiko、Takagi Akira、Katsumi Akira、Hayakawa Fumihiko、Suzuki Atsuo、Okamoto Shuichi、Kanematsu Takeshi、Matsushita Tadashi、Kojima Tetsuhito
  • Journal Title: Thromb Res. Volume: 178 Pages: 159-170
  • DOI: 10.1016/j.thromres.2019.04.004
  • Peer Reviewed / Open Access
• [Journal Article] Transcriptional landscape of B cell precursor acute lymphoblastic leukemia based on an international study of 1,223 cases. (2019)
  • 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
  • DOI: 10.1073/pnas.1814397115
  • Peer Reviewed / Open Access / Int'l Joint Research
• [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 Pages: 2263-2274
  • DOI: 10.1038/s41388-018-0573-9
  • Peer Reviewed
• [Journal Article] Pyruvate secreted from patient-derived cancer-associated fibroblasts supports survival of primary lymphoma cells. (2019)
  • Author(s): Sakamoto A, Kunou S, Shimada K, Tsunoda M, Aoki T, Iriyama C, Tomita A, Nakamura S, Hayakawa F, Kiyoi H.
  • Journal Title: Cancer Sci. Volume: 110 Pages: 269-278
  • DOI: 10.1111/cas.13873
  • Peer Reviewed / Open Access
• [Journal Article] Biology and management of primary effusion lymphoma. (2018)
  • Author(s): Shimada K, Hayakawa F, Kiyoi H
  • Journal Title: Blood Volume: 132 Pages: 1879-1888
  • DOI: 10.1182/blood-2018-03-791426
  • Peer Reviewed
• [Journal Article] BCL2 inhibitor ABT-199 and JNK inhibitor SP600125 exhibit synergistic cytotoxicity against imatinib-resistant Ph+ ALL cells. (2018)
  • Author(s): Inoue C, Sobue S, Aoyama Y, Mizutani N, Kawamoto Y, Nishizawa Y, Ichihara M, Abe A, Hayakawa F, Suzuki M, Nozawa Y, Murate T.
  • Journal Title: Biochem Biophys Rep Volume: 15 Pages: 69-75
  • DOI: 10.1016/j.bbrep.2018.07.001
  • Peer Reviewed / Open Access
• [Journal Article] Adult acute lymphoblastic leukemia: update on pathophysiology and management (2018)
  • Author(s): Hayakawa F.
  • Journal Title: Jpn. J. Clin. Hematol. Volume: 59 Issue: 5 Pages: 497-503
  • DOI: 10.11406/rinketsu.59.497
  • NAID: 130007384462
  • ISSN: 0485-1439, 1882-0824
  • Peer Reviewed
• [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 Pages: 522-526
  • DOI: 10.3324/haematol.2017.183152
  • Peer Reviewed / Open Access
• [Journal Article] Final analysis of the JALSG Ph+ALL202 study: tyrosine kinase inhibitor-combined chemotherapy for Ph+ALL (2018)
  • Author(s): Hatta Y, Mizuta S, Matsuo K, Ohtake S, Iwanaga M, Sugiura I, Doki N, Kanamori H, Ueda Y, Yoshida C, Dobashi N, Maeda T, Yujiri T, Monma F, Ito Y, Hayakawa F, Takeuchi J, Kiyoi H, Miyazaki Y, Naoe T
  • Journal Title: Ann Hematol. Volume: 97 Pages: 1535-1545
  • DOI: 10.1007/s00277-018-3323-8
  • Peer Reviewed / Open Access
• [Presentation] 悪性リンパ腫の腫瘍関連線維芽細胞由来のエクソソームはHDAC阻害剤耐性を誘導する (2020)
  • Author(s): 加賀谷 裕介, 島田 和之, 久納 俊祐, 疋田 智也, 坂本 明彦, 早川 文彦, 小根山 千歳, 清井 仁
  • Organizer: 第79回日本癌学会学術総会
• [Presentation] Endothelial colony forming cells(ECFCs)樹立法の標準化への試み (2020)
  • Author(s): 岡本 修一, 鈴木 伸明, 兼松 毅, 鈴木 敦夫, 大平 晃也, 所 真昼, 早川 友梨, 田村 彰吾, 早川 文彦, 清井 仁, 小嶋 哲人, 松下 正
  • Organizer: 第42回日本血栓止血学会学術集会
• [Presentation] Template switchingによるF8エクソン15欠損が認められた重症血友病A症例 (2020)
  • Author(s): 所 真昼, 田村 彰吾, 鈴木 伸明, 大平 晃也, 河島 史華, 早川 友梨, 早川 文彦, 岡本 修一, 兼松 毅, 勝見 章, 松下 正, 小嶋 哲人
  • Organizer: 第42回日本血栓止血学会学術集会
• [Presentation] 当施設における新生児・乳幼児に対するエミシズマブの使用経験 (2020)
  • Author(s): 兼松 毅, 鈴木 伸明, 岡本 修一, 鈴木 敦夫, 田村 彰吾, 早川 文彦, 小嶋 哲人, 清井 仁, 松下 正
  • Organizer: 第42回日本血栓止血学会学術集会
• [Presentation] C末端伸長変異型Factor XIにおける分泌異常の解析 (2020)
  • Author(s): 早川 友梨, 田村 彰吾, 鈴木 伸明, 大平 晃也, 所 真昼, 河島 史華, 早川 文彦, 高木 明, 鈴木 敦夫, 岡本 修一, 兼松 毅, 松下 正, 小嶋 哲人
  • Organizer: 第42回日本血栓止血学会学術集会
• [Presentation] スプライシング異常を引き起こす血液凝固第IX因子遺伝子イントロン1内の深部大挿入変異 (2020)
  • Author(s): 河島 史華, 田村 彰吾, 鈴木 伸明, 大平 晃也, 所 真昼, 早川 友梨, 早川 文彦, 岡本 修一, 兼松 毅, 高木 明, 松下 正, 小嶋 哲人
  • Organizer: 第42回日本血栓止血学会学術集会
• [Presentation] 1.Staurosporine induces caspase-dependent proteolysis of MEF2D-fusion protein and cell death selective to MEF2D-fusion-positive ALL cells. (2019)
  • Author(s): Naoyuki Tange, Fumihiko Hayakawa, Takahiko Yasuda, Hideyuki Yamamoto, Daiki Hirano, Shinobu Tsuzuki, Tomoki Naoe, Hitoshi Kiyoi.
  • Organizer: 61st American Society of Hematology Annual Meeting and Exposition
  • Int'l Joint Research
• [Presentation] MEF2D融合タンパクの分解を誘導する薬剤をスクリーニングするシステムの開発 (2019)
  • Author(s): Naoyuki Tange, Fumihiko Hayakawa, Takahiko Yasuda, Hideyuki Yamamoto, Daiki Hirano, Shinobu Tsuzuki, Hitoshi Kiyoi.
  • Organizer: 第81回日本血液学会学術集会
• [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
• [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] 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, Hitoshi Kiyoi
  • Organizer: 60th ASH Annual Meeting & Exposition
  • Int'l Joint Research