Identification of deregulated mTORC1 signaling in advanced chronic myelogenous leukemia

• Project/Area Number: 16K21012
• Research Category: Grant-in-Aid for Young Scientists (B)
• Allocation Type: Multi-year Fund
• Research Field: Hematology; Tumor therapeutics
• Research Institution: The University of Tokyo
• Principal Investigator: YOKOYAMA KAZUAKI 東京大学, 医科学研究所, 助教 (00647498)
• Project Period (FY): 2016-04-01 – 2019-03-31
• Project Status: Completed (Fiscal Year 2018)
• Budget Amount: ¥4,160,000 (Direct Cost: ¥3,200,000、Indirect Cost: ¥960,000); Fiscal Year 2018: ¥1,170,000 (Direct Cost: ¥900,000、Indirect Cost: ¥270,000); Fiscal Year 2017: ¥1,300,000 (Direct Cost: ¥1,000,000、Indirect Cost: ¥300,000); Fiscal Year 2016: ¥1,690,000 (Direct Cost: ¥1,300,000、Indirect Cost: ¥390,000)
• Keywords: 慢性骨髄性白血病 / チロシンキナーゼ阻害剤 / mTOR / PI3K / Akt / CML / TKI / 薬剤耐性 / 進行期慢性骨髄性白血病 / mTORC1

Outline of Final Research Achievements

Despite the success with tyrosine kinase inhibitors (TKI) in most patients with chronic myelogenous leukemia (CML), some patients with advanced phase of CML still experience TKI resistance. Previous report indicated that Pi3K/mTOR signaling acted as a bypass signaling for survival when BCR/ABL is inhibited by TKI. However, the exact mechanism by which mTOR activation remains to be elucidated. To address this question, in this study we performed comparative RNA seq approach of tumor sample in advanced CML patients in comparison to those of patients with chronic phase. As a result, we found that an mTOR component was deregulated in advanced CML, which resulted in mTOR pathway deregulation. We are now performing in vitro experiment whether mTOR pathway deregulation could be induced by such deregulation of an mTOR componet.

Academic Significance and Societal Importance of the Research Achievements

慢性骨髄性白血病（CML）の原因であるBCRABLを阻害するチロシンキナーゼ阻害剤（TKI）は殆どの慢性期CML患者に長期生存をもたらしている。一方、進行期患者ではTKI耐性を示し、その予後は不良でありその克服が課題である。主な耐性機序の解明が必要である。申請者はmTOR経路が進行期CML症例においてBypass経路として働きTKI耐性に繋がっている事を、骨髄臨床検体を用いた網羅的な遺伝子発現解析にて見出した。特に、mTORの主要構成要素の遺伝子発現の制御異常が原因と考えられた。この脱制御機序の更なる解明は、mTOR経路を標的としたTKI耐性克服法開発に繋がる可能性を有している。

Research Products

• [Journal Article] Prognostic impact of circulating tumor DNA status post-allogeneic hematopoietic stem cell transplantation in AML and MDS. (2019)
  • Author(s): Nakamura S, Yokoyama K (co-1st and co-corresponding author), Shimizu E, Yusa N, Kondoh K, Ogawa M, Takei T, Kobayashi A, Ito M, Isobe M, Konuma T, Kato S, Kasajima R, Wada Y, Inoue-Nagamura T, Yamaguchi R, Takahashi S, Imoto S, Miyano S, and Tojo A.
  • Journal Title: Blood Volume: In Press
  • Peer Reviewed
• [Journal Article] Cell lineage-oriented sequencing unveils the ontogeny of acute myeloid leukemia with myelodysplasia-related changes. (2018)
  • Author(s): Yokoyama K, Shimizu E, Yokoyama N, Nakamura S, Kasajima R, Ogawa M, Takei T, Ito M, Kobayashi A, Yamaguchi R, Imoto S, Miyano S, Tojo A.
  • Journal Title: Blood Adv. Volume: 2 Pages: 2513-2421
  • Peer Reviewed / Open Access
• [Journal Article] Phenotype-Based Gene Analysis Allowed Successful Diagnosis of X-Linked Neutropenia Associated with a Novel Wasp Mutation. (2018)
  • Author(s): Kobayashi M, Yokoyama K, Shimizu E, Yusa N, Ito M, Yamaguchi R, Imoto S, Miyano S, and Tojo A.
  • Journal Title: Ann Hematol Volume: 97 Issue: 2 Pages: 367-369
  • DOI: 10.1007/s00277-017-3134-3
  • Peer Reviewed / Int'l Joint Research
• [Journal Article] Azacitidine effectively reduces TP53-mutant leukemic cell burden in secondary acute myeloid leukemia after cord blood transplantation. (2018)
  • Author(s): Takei T, Yokoyama K, Shimizu E, Konuma T, Takahashi S, Yamaguchi R, Imoto S, Miyano S, and Tojo A.
  • Journal Title: Leukemia and Lymphoma. Volume: In press
• [Journal Article] サラセミア形質2例． (2018)
  • Author(s): 神保光児、小沼貴晶、横山和明、東條有伸
  • Journal Title: 臨床血液 Volume: In press
• [Journal Article] "Role of exosomes as a proinflammatory mediator in the development of EBV-associated lymphoma" (2018)
  • Author(s): Higuchi H, Yamakawa N, Imadome K, Yahata T, Kotaki R, Ogata J, Kakizaki M, Fujita K, Jun Lu, Yokoyama K, Okuyama K, Sato A, Takamatsu M,Kurosaki N, Mohamad AS, Azhim A, Horie R, Watanabe T, Kitamura T, Ando K, Kashiwagi T, Matsui T, Okamoto A, Handa H, Kuroda M,Nakamura N, and Kotani A.
  • Journal Title: Blood Volume: In press
• [Journal Article] Chronic inflammatory demyelinating polyneuropathy in adult T-cell leukemia-lymphoma patients following allogeneic stem cell transplantation (2018)
  • Author(s): Yoichi Imai, Mitsuhito Hirano, Koji Jimbo, Miho Ogawa, Kiyosumi Ochi, Junya Makiyama, Toyotaka Kawamata, Kazuaki Yokoyama, Takashi Tanaka, Yoshihiro Inamoto, Takahiro Fukuda, Yoshihisa Yamano, Kaoru Uchimaru, and Arinobu Tojo
  • Journal Title: Bone marrow transplantation Volume: In press
• [Journal Article] Different Clonal Dynamics of Chronic Myeloid Leukaemia between Bone Marrow and the Central Nervous System. (2017)
  • Author(s): Ogawa M, Yokoyama K, Hirano M, Jimbo K, Ochi K, Kawamata T, Ohno N, Shimizu E, Yokoyama N, Yamaguchi R, Imoto S, Uchimaru K, Takahashi N, Miyano S, Imai Y, and Tojo A.
  • Journal Title: Br J Haematol Volume: - Issue: 5 Pages: 842-845
  • DOI: 10.1111/bjh.15065
  • Peer Reviewed / Open Access
• [Journal Article] Autologous peripheral blood stem cell transplantation for double-refractory myeloma with <i>K-RAS</i> and <i>N-RAS</i> mutations (2017)
  • Author(s): 神保光児、横山和明、小川弥穂、平野光人、越智清純、小林真之、遊佐 希、清水英悟、川俣豊隆、大野伸広、山口 類、井元清哉、古川洋一、宮野 悟、今井陽一、東條有伸.
  • Journal Title: Rinsho Ketsueki Volume: 58 Issue: 12 Pages: 2380-2385
  • DOI: 10.11406/rinketsu.58.2380
  • NAID: 130006308839
  • ISSN: 0485-1439, 1882-0824
  • Peer Reviewed / Open Access
• [Presentation] Prognostic impact of circulating tumor DNA status post-allogeneic hematopoietic stem cell transplantation in acute myeloid leukemia and myelodysplastic syndrome. (2018)
  • Author(s): Nakamura S, Yokoyama K, Shimizu E, Yusa N, Ogawa M, Takei T, Kobayashi A, Ito M, Isobe M, Konuma T, Kato S, KasajimaR, Wada Y, Nagamura-Inoue T, RYamaguchi R, Takahashi S, Imoto S, Miyano S, Tojo A.
  • Organizer: 60th ASH Annual Meeting and Exposition
  • Int'l Joint Research
• [Presentation] 湿疹続発性紅皮症を伴った低悪性度B細胞性リンパ腫． (2018)
  • Author(s): 安藤匠平、横山和明、水澤 舞、近藤幹也、牧山純也、川俣豊隆、安井 寛、今井陽一、高橋 聡、東條有伸．
  • Organizer: 第8回日本血液学会関東甲信越地方会
• [Presentation] イマチニブ単剤で速やかに細胞遺伝学的寛解を得たFIP1L1-PDGFRA陽性AMLの一例 (2018)
  • Author(s): 近藤幹也、牧山純也、安藤匠平、水澤 舞、川俣豊隆、横山和明、安井 寛、今井陽一、東條有伸．
  • Organizer: 第8回日本血液学会関東甲信越地方会
• [Presentation] 血中循環腫瘍DNAは造血器腫瘍の個別化バイオマーカーとなり得るか？ (2017)
  • Author(s): 中村聡介、横山和明、遊佐 希、小林麻子、伊藤美香、小林真之、神保光児、小川弥穂、平野光人、武井智美、田上 晋、越智清純、磯部優理、川俣豊隆、小沼貴晶、加藤せい子、清水英悟、大野伸広、高橋 聡、山口 類、井元清哉、古川洋一、宮野 悟、今井陽一、東條有伸．
  • Organizer: 第79回日本血液学会学術集会
• [Presentation] Cell lineage-oriented clinical sequencing unveils distinct clonal ontogeny of acute myeloid leukemia with myelodysplasia-related changes. (2017)
  • Author(s): Yokoyama K, Yusa N, Kobayashi A, Kobayashi M, Kasajima R, Yui H, Shimizu E, Yamaguchi R, Imoto S, Furukawa Y, Miyano S, and Tojo A.
  • Organizer: American Association for Cancer Research (AACR) Annual Meeting
  • Int'l Joint Research
• [Presentation] Personalized Circulating Tumor DNA Predicts Relapse after Allogeneic Hematopoietic Stem Cell Transplantation in Acute Myeloid Leukemia and Myelodysplastic Syndrome. (2017)
  • Author(s): Nakamura S, Yokoyama K, Yusa N, Ogawa M, Takei T, Kobayashi A, Ito M, Kobayashi M, Jimbo K, Tanoue S, Takaaki K, Kato S, Shimizu E, Kasajima R, Wada Y, Yamaguchi R, Imoto S, Furukawa YNagamura-Inoue T, Takahashi S, , Miyano S, Tojo A.
  • Organizer: American Society of Hematology (ASH) 59th Annual Meeting and Exposition.
  • Int'l Joint Research
• [Presentation] Personalized Circulating Tumor DNA Dynamically Predicts Response and/or Relapse in Hematological Malignancies. (2017)
  • Author(s): Nakamura S, Yokoyama K, Yusa N, Ogawa M, Takei T, Kobayashi A, Ito M, Kobayashi M, Shimizu E, Kasajima R, Wada Y, Yamaguchi R, Imoto S, Furukawa Y, Nagamura-Inoue T, Miyano S, Tojo A.
  • Organizer: American Society of Hematology (ASH) 59th Annual Meeting and Exposition.
  • Int'l Joint Research
• [Presentation] A novel mutant WASp in X-linked neutropenia partially recapitulates defective neutrophil production through its expression in WASp-deficient NB4 Cells. (2017)
  • Author(s): Kobayashi M, Chanda B, Futami M, Yamashita M, Hirano M, Yokoyama K, Imai Y, Shimizu E, Yusa N, Yamaguchi R, Imoto S, Miyano S, Tojo A.
  • Organizer: American Society of Hematology (ASH) 59th Annual Meeting and Exposition.
  • Int'l Joint Research
• [Presentation] Exploratory introduction of cognitive computing to clinical sequencing in hematological malignancies (2016)
  • Author(s): Kazuaki Yokoyama, et al
  • Organizer: The 78th Annual Meeting of the Japanese Society of Hematology
  • Place of Presentation: パシフィコ横浜
• [Book] 人工知能の臨床応用-血液疾患-,日本病院薬剤師会雑誌 (2018)
  • Author(s): 小川弥穂、横山和明、東條有伸.
  • Total Pages: 5
  • Publisher: 日本病院薬剤師会
• [Book] 血液がんの臨床シークエンスにおける人工知能Watsonの活用. 医学のあゆみ (2017)
  • Author(s): 横山和明、東條有伸
  • Total Pages: 4
  • Publisher: 医歯薬出版株式会社
• [Book] 人口知能を用いた臨床シークエンス. 腫瘍内科 (2017)
  • Author(s): 横山和明、東條有伸
  • Total Pages: 5
  • Publisher: 科学評論社
• [Book] 人工知能ワトソンを用いた疾患診断. 感染炎症免疫 (2017)
  • Author(s): 中村聡介、横山和明
  • Total Pages: 3
  • Publisher: 医薬の門社
• [Book] 腫瘍内科 (2017)
  • Author(s): 横山和明 東條有伸
  • Total Pages: 6
  • Publisher: 科学評論社