Molecular pathologic elucidation to become usefulness and the choice grounds of the novel FLT3 inhibitor

2019 Fiscal Year Annual Research Report

• Project/Area Number: 17K09921
• Research Institution: Nagoya University
• Principal Investigator: 清井 仁 名古屋大学, 医学系研究科, 教授 (90314004)
• Project Period (FY): 2017-04-01 – 2020-03-31
• Keywords: 急性骨髄性白血病 / FLT3 / 分子標的薬 / 耐性

Outline of Annual Research Achievements

32Dに導入したITD-FLT3発現細胞、野生型FLT3の発現量の異なる2種類の32D ITD-FLT3/野生型FLT3共発現細胞を用いて、5種類のFLT3阻害剤の増殖阻害活性とFL刺激の阻害剤感受性に与える影響について評価した。ITD-FLT3単独発現細胞では、全ての化合物において、FL追加による影響はほとんど認められなかった。一方、野生型FLT3/ITD-FLT3共発現細胞のGI50値はFL無添加時と比較して、FF-10101で6.2倍、gilteritinibで8.1倍、quizartinibで17.7倍、crenolanibでは3.4倍に増加し、増殖阻害活性の減弱が認められた。
FLT3遺伝子変異陽性AML-PDXマウスモデルを作成し、長期間FLT3阻害剤で治療することで治療効果を経時的に観察し、その感受性と野生型FLT3発現について解析を行った。治療開始70日目には、未治療マウスのCD34-/38+分画ではITD-FLT3アレル比は8.03と高く、CD34-/38-細胞分画では、未治療マウス、FLT3阻害剤投与マウスいずれにおいても ITD-FLT3アレル比は同様に低かった。治療を継続した群では、治療開始後174日目の末梢血中のhCD45陽性細胞はquizartinib, gilteritinib治療マウスでほとんど検出されず、そのITD-FLT3アレル比はそれぞれ0.14 , 0.26と野生型FLT3優位な細胞が残存していた。
これらより、quizartinib, gilteritinibによる治療では、ITD-FLT3アレル比が高い細胞はFLT3阻害剤に高い感受性を示す一方で、長期間治療を継続しても野生型FLT3分子の発現が高い白血病細胞が最終的に残存することが、再発や耐性化獲得につながっている可能性が示唆された。

Research Products

• [Journal Article] JSH Practical Guidelines for Hematological Malignancies, 2018: I. Leukemia-1. Acute myeloid leukemia (AML). (2020)
  • Author(s): Kiyoi H, Yamaguchi H, Maeda Y, Yamauchi T
  • Journal Title: Int J Hematol Volume: 111 Pages: 595-613
  • DOI: 10.1007/s12185-020-02856-3
  • Peer Reviewed
• [Journal Article] Rituximab, cyclophosphamide, doxorubicin, vincristine, and prednisolone combined with high-dose methotrexate plus intrathecal chemotherapy for newly diagnosed intravascular large B-cell lymphoma (PRIMEUR-IVL): a multicentre, single-arm, phase 2 trial (2020)
  • Author(s): Shimada K, Yamaguchi M, Atsuta Y, Kiyoi H, Suzuki R, Tokunaga T, Nakamura S, Kinoshita T
  • Journal Title: The Lancet Oncology Volume: 21 Pages: 593～602
  • DOI: 10.1016/S1470-2045(20)30059-0
  • 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): Ogawa Mika、Suzuki Nobuaki、Takahashi Nobunori、Tamura Shogo、Suzuki Atsuo、Suzuki Sachiko、Hattori Yuua、Kakihara Misaki、Kanematsu Takeshi、Kojima Toshihisa、Katsumi Akira、Hayakawa Fumihiko、Kojima Tetsuhito、Ishiguro Naoki、Kiyoi Hitoshi、Matsushita Tadashi
  • Journal Title: Thrombosis Research Volume: 188 Pages: 103～105
  • DOI: 10.1016/j.thromres.2020.01.003
  • Peer Reviewed
• [Journal Article] Successful Introduction of Peritoneal Dialysis in an End-stage Renal Failure Patient with Idiopathic Aplastic Anemia (2020)
  • Author(s): Suzuki Yasuhiro、Mizuno Masashi、Sakata Fumiko、Kojima Hiroshi、Sato Yuka、Kishimoto Mayuko、Suzuki Nobuaki、Kinashi Hiroshi、Saito Shoji、Katsuno Takayuki、Kosugi Tomoki、Maruyama Shoichi、Murata Makoto、Kiyoi Hitoshi、Ito Yasuhiko
  • Journal Title: Internal Medicine Volume: 59 Pages: 683～687
  • DOI: 10.2169/internalmedicine.3775-19
  • Peer Reviewed
• [Journal Article] Anti-thyroid antibodies and thyroid echo pattern at baseline as risk factors for thyroid dysfunction induced by anti-programmed cell death-1 antibodies: a prospective study (2020)
  • Author(s): Okada Norio、Iwama Shintaro、Kiyoi Hitoshi、Gotoh Momokazu、Ando Yuichi、Akiyama Masashi、Hasegawa Yoshinori、Arima Hiroshi
  • Journal Title: British Journal of Cancer Volume: 122 Pages: 771～777
  • DOI: 10.1038/s41416-020-0736-7
  • Peer Reviewed
• [Journal Article] Phase 1b/2 study of blinatumomab in Japanese adults with relapsed/refractory acute lymphoblastic leukemia (2020)
  • Author(s): Kiyoi Hitoshi、Morris Joan D、Oh Iekuni、Maeda Yoshinobu、Minami Hironobu、Miyamoto Toshihiro、Sakura Toru、Iida Hiroatsu、Tuglus Catherine A、Chen Yuqi、Dos Santos Cedric、Kalabus James、Anderson Abraham、Hata Tomoko、Nakashima Yasuhiro、Kobayashi Yukio
  • Journal Title: Cancer Science Volume: 111 Pages: 1314～1323
  • DOI: 10.1111/cas.14322
  • Peer Reviewed / Open Access
• [Journal Article] Prospective evaluation of prognostic impact of KIT mutations on acute myeloid leukemia with RUNX1-RUNX1T1 and CBFB-MYH11 (2020)
  • Author(s): Ishikawa Yuichi、Kawashima Naomi、Atsuta Yoshiko、Kiyoi Hitoshi
  • Journal Title: Blood Advances Volume: 4 Pages: 66～75
  • DOI: 10.1182/bloodadvances.2019000709
  • Peer Reviewed / Open Access
• [Journal Article] FLT3 mutations in acute myeloid leukemia: Therapeutic paradigm beyond inhibitor development (2019)
  • Author(s): Kiyoi Hitoshi、Kawashima Naomi、Ishikawa Yuichi
  • Journal Title: Cancer Science Volume: 111 Pages: 312～322
  • DOI: 10.1111/cas.14274
  • Peer Reviewed / Open Access
• [Journal Article] Successful Perioperative Combination of High-Dose FVIII Therapy Followed by Emicizumab in a Patient with Hemophilia A with Inhibitors (2019)
  • Author(s): Okamoto Shuichi、Suzuki Nobuaki、Suzuki Atsuo、Suzuki Sachiko、Tamura Shogo、Suzuki Mochihito、Takahashi Nobunori、Kojima Toshihisa、Kanematsu Takeshi、Kojima Tetsuhito、Kiyoi Hitoshi、Ishiguro Naoki、Matsushita Tadashi
  • Journal Title: TH Open Volume: 03 Pages: e364～e366
  • DOI: 10.1055/s-0039-3401001
  • Peer Reviewed / Open Access
• [Journal Article] ZNF384‐fusion proteins have high affinity for the transcriptional coactivator EP300 and aberrant transcriptional activities (2019)
  • Author(s): Yamamoto Hideyuki、Hayakawa Fumihiko、Yasuda Takahiko、Odaira Koya、Minamikawa Yuka、Tange Naoyuki、Hirano Daiki、Kojima Yuki、Morishita Takanobu、Tsuzuki Shinobu、Naoe Tomoki、Kiyoi Hitoshi
  • Journal Title: FEBS Letters Volume: 593 Pages: 2151～2161
  • DOI: 10.1002/1873-3468.13506
  • Peer Reviewed
• [Journal Article] Defective Epstein?Barr virus in chronic active infection and haematological malignancy (2019)
  • Author(s): Okuno Yusuke、Kiyoi Hitoshi、Kato Seiichi、Nakamura Shigeo、Morishima Satoko、Yoshikawa Tetsushi、Fujiwara Shigeyoshi、Shimizu Norio、Isobe Yasushi、Noguchi Masaaki、Kikuta Atsushi、Iwatsuki Keiji、Takahashi Yoshiyuki、Kojima Seiji、Ogawa Seishi、Kimura Hiroshi
  • Journal Title: Nature Microbiology Volume: 4 Pages: 404～413
  • DOI: 10.1038/s41564-018-0334-0
  • Peer Reviewed
• [Journal Article] Pyruvate secreted from patient-derived cancer-associated fibroblasts supports survival of primary lymphoma cells (2019)
  • Author(s): Sakamoto Akihiko、Kunou Shunsuke、Shimada Kazuyuki、Tsunoda Makoto、Aoki Tomohiro、Iriyama Chisako、Tomita Akihiro、Nakamura Shigeo、Hayakawa Fumihiko、Kiyoi Hitoshi
  • Journal Title: Cancer Science Volume: 110 Pages: 269～278
  • DOI: 10.1111/cas.13873
  • Peer Reviewed / Open Access
• [Journal Article] Clinical significance of ASXL2 and ZBTB7A mutations and C-terminally truncated RUNX1-RUNX1T1 expression in AML patients with t(8;21) enrolled in the JALSG AML201 study (2019)
  • Author(s): Kawashima N, Akashi A, Nagata Y, Kihara R, Ishikawa Y, Kiyoi H
  • Journal Title: Ann Hematol Volume: 98 Pages: 83～91
  • DOI: 10.1007/s00277-018-3492-5
  • Peer Reviewed
• [Journal Article] Tamibarotene maintenance improved relapse-free survival of acute promyelocytic leukemia: a final result of prospective, randomized, JALSG-APL204 study (2019)
  • Author(s): Takeshita Akihiro、Kiyoi Hitoshi、Ohtake Shigeki、Matsumura Itaru、Naoe Tomoki、Miyazaki Yasushi
  • Journal Title: Leukemia Volume: 33 Pages: 358～370
  • DOI: 10.1038/s41375-018-0233-7
  • 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 Daiki、Hayakawa Fumihiko、Yasuda Takahiko、Tange Naoyuki、Yamamoto Hideyuki、Kojima Yuki、Morishita Takanobu、Imoto Naoto、Tsuzuki Shinobu、Mano Hiroyuki、Naoe Tomoki、Kiyoi Hitoshi
  • Journal Title: Oncogene Volume: 38 Pages: 2263～2274
  • DOI: 10.1038/s41388-018-0573-9
  • Peer Reviewed
• [Journal Article] Exome analysis of treatment‐related AML after APL suggests secondary evolution (2019)
  • Author(s): Wang Tianjiao、Jacoby Meagan A、Duncavage Eric J、Miller Christopher A、Heath Sharon、Rahme Ramy、Fenaux Pierre、Ades Lionel、Renneville Aline、Cassinat Bruno、Takeshita Akihiro、Asou Norio、Miyazaki Yasushi、Kiyoi Hitoshi、Ravandi Farhad、Westervelt Peter、Wartman Lukas D、Welch John S
  • Journal Title: British Journal of Haematology Volume: 185 Pages: 984～987
  • DOI: 10.1111/bjh.15681
  • Peer Reviewed / Int'l Joint Research
• [Journal Article] Transcriptional landscape of B cell precursor acute lymphoblastic leukemia based on an international study of 1,223 cases (2019)
  • Author(s): Li Jian-Feng、Dai Yu-Ting、Kiyoi Hitoshi、Matsumura Itaru、Miyazaki Yasushi、Olsson Linda、Tan Ah Moy、Ariffin Hany、Chen Jing、Takita Junko、Yasuda Takahiko、Mano Hiroyuki、Johansson Bertil、Yang Jun J、Yeoh Allen Eng-Juh、Hayakawa Fumihiko、Chen Zhu、Pui Ching-Hon、Fioretos Thoas、Chen Sai-Juan、Huang Jin-Yan
  • Journal Title: Proceedings of the National Academy of Sciences Volume: 115 Pages: E11711～E11720
  • DOI: 10.1073/pnas.1814397115
  • Peer Reviewed / Int'l Joint Research
• [Journal Article] Quantitative Assessment of T Cell Clonotypes in Human Acute Graft-versus-Host Disease Tissues (2019)
  • Author(s): Koyama Daisuke、Murata Makoto、Hanajiri Ryo、Akashi Tomohiro、Okuno Shingo、Kamoshita Sonoko、Julamanee Jakrawadee、Takagi Erina、Miyao Kotaro、Sakemura Reona、Goto Tatsunori、Terakura Seitaro、Nishida Tetsuya、Kiyoi Hitoshi
  • Journal Title: Biology of Blood and Marrow Transplantation Volume: 25 Pages: 417～423
  • DOI: 10.1016/j.bbmt.2018.10.012
  • Peer Reviewed
• [Presentation] FLT3変異陽性AML細胞における野生型FLT3の発現とFLT3阻害剤の阻害活性 (2019)
  • Author(s): 金貞姫, 石川裕一, 川島直実, 中島麻梨絵, 原田靖彦, 牛島洋子, 清井仁
  • Organizer: 日本血液学会年次総会
• [Presentation] FLT3-ITD 変異陽性AML に対する第一寛解期での同種造血幹細胞移植； JALSG AML209-FLT3-SCT Study 結果 (2019)
  • Author(s): 川島直実, 石川裕一, 熱田由子, 澤正史, 小澤幸泰, 林正樹, 河野彰夫, 冨田章裕,前田智也, 堺田惠美子, 臼杵憲祐, 萩原真紀, 金森平和, 松岡広, 小林美希,麻生範雄, 大竹茂樹, 松村到, 宮﨑泰司, 直江知樹, 清井仁
  • Organizer: 日本血液学会年次総会
• [Presentation] 急性骨髄性白血病に対するレセプター型チロシンキナーゼの細胞膜発現阻害薬の開発とその有効性 (2019)
  • Author(s): 中島麻梨絵, 江嵜正浩, 石川裕一, 川島直実, 金貞姫, 原田靖彦, 牛島洋子, 石井俊彦, 森聖寿, 清井仁
  • Organizer: 日本血液学会年次総会
• [Presentation] 急性骨髄性白血病白血病に対するクリニカルシークエンス実行可能性を検証する多施設共同研究 (2019)
  • Author(s): 横山寿行, 安田貴彦, 石川裕一, 臼杵憲祐, 矢野真吾, 伊藤良和, 康史朗, 木口亨, 宮田泰彦, 清井仁, 松村到, 宮﨑泰司, 服部浩佳, 西島大, 山本松雄, 齋藤明子, 倉橋浩樹, 白石友一, 宮野悟, 真田昌, 小川誠司, 堀部敬三
  • Organizer: 日本血液学会年次総会
• [Presentation] AMLにおけるFLT3阻害剤の効果予測バイオマーカーと至適治療法の開発 (2019)
  • Author(s): 原田靖彦, 石川裕一, 川島直実, 金貞姫, 中島麻梨絵, 足立佳也, 牛島洋子, 清井仁
  • Organizer: 日本血液学会年次総会
• [Presentation] Development of Predictive Biomarker and Optimal Treatment Strategy with FLT3 Inhibitors in Acute Myeloid Leukemia (2019)
  • Author(s): Jeong Hui Kim, Yasuhiko Harada, Yuichi Ishikawa, Naomi Kawashima, Marie Nakashima, Yoko Ushijima, Takahiro Nishiyama, Tatsunori Goto, Nobuaki Fukushima, Rika Kihara, Tomohiro Kajiguchi, Koichi Watamoto, Akio Kohno, Kunio Kitamura, Yukiyasu Ozawa, Hitoshi Kiyoi
  • Organizer: 米国血液学会年次総会
  • Int'l Joint Research
• [Presentation] Prospective Evaluation of Allogeneic HSCT at the First Remission for Younger Adults with FLT3 -ITD Positive Acute Myeloid Leukemia: The JALSG AML209-FLT3-SCT Study (2019)
  • Author(s): Naomi Kawashima, Yuichi Ishikawa, Yoshiko Atsuta, Hitoshi Kiyoi
  • Organizer: 米国血液学会年次総会
  • Int'l Joint Research
• [Presentation] Phase I Study of Cord Blood Transplantation with Intra-Bone Marrow Injection of Mesenchymal Stem Cells (2019)
  • Author(s): Tatsunori Goto, Makoto Murata, Tetsuya Nishida, Seitaro Terakura, Sonoko Kamoshita, Yuichi Ishikawa, Yoko Ushijima, Yoshiya Adachi, Katsuyoshi Kato, Akihiro Hirakawa, Satoshi Nishiwaki, Nobuhiro Nishio, Yoshiyuki Takahashi, Yoshihisa Kodera, Tadashi Matsushita, Hitoshi Kiyoi
  • Organizer: 米国血液学会年次総会
  • Int'l Joint Research
• [Presentation] 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, Hitoshi Kiyoi
  • Organizer: 米国血液学会年次総会
  • Int'l Joint Research
• [Presentation] Guided Polarization of iPSC-Derived CD4SP Helper T Cells By CRISPR/Cas9-Based Genome-Editing (2019)
  • Author(s): Hisashi Yano, Tokuyuki Shinohara, Keiko Koga, Shoichi Iriguchi, Yasuyuki Miyake, Xuewei Song, Megumi Tada, Yoshiaki Kassai, Hitoshi Kiyoi, Shin Kaneko
  • Organizer: 米国血液学会年次総会
  • Int'l Joint Research
• [Presentation] FF-10101 Retains Potent Inhibitory Activities Against Resistant Mutations to FLT3 Inhibitors, Newly Identified in Random Mutagenesis Screens (2019)
  • Author(s): Yuichi Ishikawa, Koichi Saito, Naomi Kawashima, Michie Morimoto, Hidetoshi Murao, Daisuke Terada, Takeshi Yamaura, Shinji Hagiwara, Hitoshi Kiyoi
  • Organizer: 米国血液学会年次総会
  • Int'l Joint Research
• [Presentation] Discovery of a Novel Dihydroorotate Dehydrogenase Inhibitor That Induces Differentiation and Overcomes Ara-C Resistance of Acute Myeloid Leukemia Cells (2019)
  • Author(s): Satoshi Kitazawa, Yukiko Ishii, Keiko Makita-Suzuki, Koichi Saito, Kensuke Takayanagi, Hiromi Sugihara, Shun Matsuda, Takayuki Yamakawa, Yasuhiro Tsutsui, Tadashi Tanaka, Tomohisa Hatta, Tohru Natsume, Toru Kondo, Yuichi Ishikawa, Shinji Hagiwara, Hitoshi Kiyoi
  • Organizer: 米国血液学会年次総会
  • Int'l Joint Research
• [Presentation] Favorable Outcomes of Newly Diagnosed Intravascular Large B-Cell Lymphoma Patients Treated with R-CHOP Combined with High-Dose Methotrexate Plus Intrathecal Chemotherapy: Results from a Multicenter Phase 2 Trial (PRIMEUR-IVL) (2019)
  • Author(s): Kazuyuki Shimada, Hitoshi Kiyoi, Ritsuro Suzuki, Takashi Tokunaga, Shigeo Nakamura, Tomohiro Kinoshita
  • Organizer: 米国血液学会年次総会
  • Int'l Joint Research
• [Presentation] Prospective Comparison of Azacitidine Treatment between 7-Days and 5-Days Schedules for Patients with Higher-Risk Myelodysplastic Syndromes; Results of Japan Adult Leukemia Study Group MDS212 Trial (2019)
  • Author(s): Toru Kiguchi, Hitoshi Kiyoi, Tomoki Naoe, Yasushi Miyazaki
  • Organizer: 米国血液学会年次総会
  • Int'l Joint Research
• [Presentation] The Optimal Treatment Strategy for Adult Patients with Philadelphia Chromosome-Negative Acute Lymphoblastic Leukemia in First Complete Remission in the Era of High-Intensity Chemotherapy (2019)
  • Author(s): Shinichi Kako,Hitoshi Kiyoi, Itaru Matsumura, Yasushi Miyazaki, Yoshiko Atsuta
  • Organizer: 米国血液学会年次総会
  • Int'l Joint Research