Novel therapeutic approaches targeting intracellular trafficking of RTK mutants in acute myeloid leukemia cells.

• Project/Area Number: 25461439
• Research Category: Grant-in-Aid for Scientific Research (C)
• Allocation Type: Multi-year Fund
• Section: 一般
• Research Field: Hematology
• Research Institution: Kinki University
• Principal Investigator: TANAKA Hirokazu 近畿大学, 医学部, 講師 (40360846)
• Co-Investigator(Kenkyū-buntansha): MATSUMURA Itaru 近畿大学, 医学部, 教授 (00294083) ; HIRASE Chikara 近畿大学, 医学部, 医学部講師 (30548590)
• Project Period (FY): 2013-04-01 – 2016-03-31
• Project Status: Completed (Fiscal Year 2015)
• Budget Amount: ¥5,200,000 (Direct Cost: ¥4,000,000、Indirect Cost: ¥1,200,000); Fiscal Year 2015: ¥1,170,000 (Direct Cost: ¥900,000、Indirect Cost: ¥270,000); Fiscal Year 2014: ¥1,560,000 (Direct Cost: ¥1,200,000、Indirect Cost: ¥360,000); Fiscal Year 2013: ¥2,470,000 (Direct Cost: ¥1,900,000、Indirect Cost: ¥570,000)
• Keywords: 白血病 / 受容体 / 細胞内輸送 / 分子標的 / 膜輸送 / 造血因子

Outline of Final Research Achievements

FLT3-ITD and KIT D816V mutation are frequently found in AML and associated with poor prognosis. In this study, we evaluated the anti-leukemic effects of an inhibitor of membrane trafficking, chlorpromazine (CPZ).
Recent studies demonstrated that these oncogenic RTKs are mislocalized in the cytoplasm, where they transmit aberrant signals to downstream. CPZ disrupted the intracellular trafficking of RTK mutants, and significantly suppressed activities of RTK mutants and their downstream molecules. Consequently, CPZ inhibited the growth and survival of AML cells with mutant RTK in a dose-dependent manner. In xenotransplantation models, administration of CPZ significantly reduced engraftment of AML cells, and also showed the cytotoxic effect to AML stem cells, while displaying minimal toxicity to normal hematopoietic cells. These results suggest that CPZ would be a promising therapeutic drug to eradicate AML cells with an established safety profile.

Research Products

• [Journal Article] ESAM is a novel human hematopoietic stem cell marker associated with a subset of human leukemias. (2016)
  • Author(s): Ishibashi T, Yokota T, Tanaka H, Ichii M, Sudo T, Satoh Y, Doi Y, Ueda T, Tanimura A, Hamanaka Y, Ezoe S, Shibayama H, Oritani K, Kanakura Y.
  • Journal Title: Experimental Hematology Volume: 44 Issue: 4 Pages: 269-281
  • DOI: 10.1016/j.exphem.2015.12.010
  • Peer Reviewed / Open Access / Acknowledgement Compliant
• [Journal Article] Mice doubly-deficient in the Arf GAPs SMAP1 and SMAP2 exhibit embryonic lethality (2015)
  • Author(s): Sumiyoshi M, Rai S, Tanaka H, Matsumura I, et al.
  • Journal Title: FEBS Lett. Volume: 589 Issue: 19PartB Pages: 2754-2762
  • DOI: 10.1016/j.febslet.2015.07.050
  • Peer Reviewed / Open Access
• [Journal Article] HIV-negative Primary Bone Marrow Hodgkin Lymphoma Manifesting with a High Fever Associated with Hemophagocytosis as the Initial Symptom: A Case Report and Review of the Previous Literature (2015)
  • Author(s): Morita Y, Matsumura I,et al.
  • Journal Title: Internal Medicine Volume: 54 Issue: 11 Pages: 1393-1396
  • DOI: 10.2169/internalmedicine.54.3770
  • NAID: 130005072946
  • ISSN: 0918-2918, 1349-7235
  • Peer Reviewed / Open Access
• [Journal Article] Aleukemic solitary cutaneous myeloid sarcoma. (2015)
  • Author(s): Yanagihara M,Tanaka H,Matsumura I, Kawada A,et al.
  • Journal Title: J Dermatol. Volume: 42 Issue: 8 Pages: 844-845
  • DOI: 10.1111/1346-8138.12924
  • Peer Reviewed
• [Journal Article] Molecular mechanisms in the resistance of CML stem cells to tyrosine kinase inhibitors and novel targets for achieving a cure (2015)
  • Author(s): Tanaka H, Hirase C, Matsumura I.
  • Journal Title: Rinsho Ketsueki Volume: 56 Issue: 2 Pages: 139-149
  • DOI: 10.11406/rinketsu.56.139
  • NAID: 130004920712
  • ISSN: 0485-1439, 1882-0824
  • Peer Reviewed / Open Access
• [Journal Article] The preventative effects of recombinant thrombomodulin on transplantation- associated coagulopathy after allogeneic hematopoietic stem cell transplantation (2014)
  • Author(s): Nomura S, Ishii K, Maeda Y, Katayama Y, Yagi H, Fujishima N, Ota S, Seki M, Okada M, Ikezoe T, Hayashi K, Fujita S, Satake A, Ito T, Kyo T, Ishida Y, Chiba S, Ogawa H, Tanimoto M, Sawada K
  • Journal Title: Journal of Stem Cell Research & Therapy Volume: 4 Issue: 1 Pages: 247-247
  • DOI: 10.1007/s12185-014-1696-6
  • Peer Reviewed / Open Access
• [Journal Article] Clathrin assembly protein CALM Plays a Critical Role in KIT Signaling by Regulating Its Cellular Transport from Early to Late Endosomes in Hematopoietic Cells. (2014)
  • Author(s): Shinya Rai, Hirokazu Tanaka*, Mai Suzuki , Honami Ogoh, Yasuhiro Taniguchi, Yasuyoshi Morita, Takahiro Shimada, Akira Tanimura, Keiko Matsui, Takafumi Yokota, Kenji Oritani, Kenji Tanabe, Toshio Watanabe, Yuzuru Kanakura, and Itaru Matsumura
  • Journal Title: PLoS ONE Volume: 該当しない Issue: 10 Pages: 0109441-0109441
  • DOI: 10.1371/journal.pone.0109441
  • Peer Reviewed / Open Access / Acknowledgement Compliant
• [Journal Article] Limited value of the international staging system for predicting long-term outcome of transplant-ineligible, newly diagnosed, symptomatic multiple myeloma in the era of novel agents. (2014)
  • Author(s): Kuroda J, Shimura Y, Ohta K, Tanaka H, Shibayama H, Kosugi S, Fuchida S, Kobayashi M, Kaneko H, Uoshima N, Ishii K, Nomura S, Taniwaki M, Takaori-Kondo A, Shimazaki C, Tsudo M, Hino M, Matsumura I, Kanakura Y; Kansai Myeloma Forum Investigators.
  • Journal Title: Int J Hematol. Volume: 99 Issue: 4 Pages: 441-449
  • DOI: 10.1007/s12185-014-1539-5
  • Peer Reviewed / Open Access
• [Journal Article] The anti-apoptotic gene Anamorsin is essential for both autonomous and extrinsic regulation of murine fetal liver hematopoiesis. (2014)
  • Author(s): Tanimura A, Shibayama H, Hamanaka Y, Fujita N, Ishibashi T, Sudo T, Yokota T, Ezoe S, Tanaka H, Matsumura I, Oritani K, Kanakura Y.
  • Journal Title: Exp Hematol. Volume: 42 Issue: 5 Pages: 410-422
  • DOI: 10.1016/j.exphem.2014.01.002
  • Peer Reviewed / Open Access
• [Journal Article] Impaired hematopoietic differentiation of RUNX1-mutated induced pluripotent stem cells derived from FPD/AML patients (2014)
  • Author(s): Sakurai M, Kunimoto H, Watanabe N, Fukuchi Y, Yuasa S, Yamazaki S, Nishimura T, Sadahira K, Fukuda K, Okano H, Nakauchi H, Morita Y, Matsumura I, Kudo K, Ito E, Ebihara Y, Tsuji K, Harada Y, Harada H, Okamoto S, Nakajima H
  • Journal Title: Leukemia Volume: 28 Issue: 12 Pages: 2344-54
  • DOI: 10.1038/leu.2014.136
  • Peer Reviewed / Open Access
• [Journal Article] 慢性骨髄性白血病の治療 (2014)
  • Author(s): 松村 到
  • Journal Title: 日本内科学会雑誌 Volume: 103 Pages: 2264-2268
  • Peer Reviewed / Open Access
• [Journal Article] 骨髄系の白血病幹細胞 (2014)
  • Author(s): 田中宏和、松村 到
  • Journal Title: 血液内科 Volume: 68 Pages: 572-579
  • Peer Reviewed / Open Access
• [Journal Article] 骨髄系の白血病幹細胞 (2014)
  • Author(s): 田中宏和、松村 到
  • Journal Title: 医学のあゆみ Volume: 250 Pages: 33-41
  • Peer Reviewed / Open Access
• [Journal Article] 慢性骨髄性白血病におけるELN2013 (2014)
  • Author(s): 平瀨主税、田中宏和、松村 到
  • Journal Title: 血液内科 Volume: 68 Pages: 399-404
  • Peer Reviewed / Open Access
• [Journal Article] 慢性骨髄性白血病 (2014)
  • Author(s): 宮武淳一、平瀨主税、松村 到
  • Journal Title: 臨床腫瘍プラクティス Volume: 10 Pages: 43-48
  • Peer Reviewed / Open Access
• [Journal Article] The Satb1 protein directs hematopoietic stem cell differentiation toward lymphoid lineages. (2013)
  • Author(s): Satoh Y, Yokota T, Sudo T, Kondo M, Lai A, Kincade PW, Kouro T, Iida R, Kokame K, Miyata T, Habuchi Y, Matsui K, Tanaka H, Matsumura I, Oritani K, Kohwi-Shigematsu T, Kanakura Y.
  • Journal Title: Immunity Volume: 38 Issue: 6 Pages: 1105-1115
  • DOI: 10.1016/j.immuni.2013.05.014
  • Peer Reviewed
• [Journal Article] Successful anticoagulant therapy for two pregnant PNH patients, and prospects for the eculizumab era. (2013)
  • Author(s): Morita Y, Nishimura J, Shimada T, Tanaka H, Serizawa K, Taniguchi Y, Tsurutani M, Kanakura Y, Matsumura I
  • Journal Title: Int J Hematol. Volume: 97 Issue: 4 Pages: 491-497
  • DOI: 10.1007/s12185-013-1302-3
  • NAID: 10031168516
  • Peer Reviewed
• [Journal Article] Successful allogeneic hematopoietic stem cell transplantation in a young patient with Richter syndrome presenting with chronic lymphocytic leukemia and diffuse large B-cell lymphoma with different cell origins. (2013)
  • Author(s): Rai S, Matsuda M, Yamairi N, Eguchi G, Iwanaga T, Morita Y, Tanaka H, Tatsumi Y, Ashida T, Matsumura I.
  • Journal Title: Intern Med. Volume: 52 Pages: 273-276
  • NAID: 130003365858
  • Peer Reviewed
• [Journal Article] 慢性好酸球性白血病、非特定型 (2013)
  • Author(s): 田中宏和、平瀨主税、松村 到
  • Journal Title: 日本臨床 Volume: 23 Pages: 67-72
• [Journal Article] 白血病 (2013)
  • Author(s): 田中宏和、松村 到
  • Journal Title: アニムス Volume: 75 Pages: 11-15
• [Presentation] Analysis of MECP regimen with relapsed or refractory malignant lymphoma in our institution (2015)
  • Author(s): Kentaro Serizawa,Hirokazu Tanaka,Itaru Matsumura,et al.
  • Organizer: 第77回日本血液学会学術集会
  • Place of Presentation: 石川県立音楽堂、ANAクラウンプラザホテル金沢
  • Year and Date: 2015-10-16
• [Presentation] Retrospective analysis of MM patients with dual refractory to bortezomib and IMiDs in KMF registry (2015)
  • Author(s): Takae Kohara,Hirokazu Tanaka,Itaru Matsumura,Akifumi Takaori-Kondo,et al.
  • Organizer: 第77回日本血液学会学術集会
  • Place of Presentation: 石川県立音楽堂、ANAクラウンプラザホテル金沢
  • Year and Date: 2015-10-16
• [Presentation] Dose early tretment improve the outcome of patients with transplant-ineligible symptomaic myeloma? (2015)
  • Author(s): Aya Nakaya,Hirokazu Tanaka,Itaru Matsumura,Akifumi Takaori-Kondo,et al.
  • Organizer: 第77回日本血液学会学術集会
  • Place of Presentation: 石川県立音楽堂、ANAクラウンプラザホテル金沢
  • Year and Date: 2015-10-16
• [Presentation] 症候性骨髄腫969症例における腎障害の後方視的解析（関西骨髄腫フォーラム） (2015)
  • Author(s): 金子仁臣、田中宏和、松村 到、高折晃史 他
  • Organizer: 第77回日本血液学会学術集会
  • Place of Presentation: 石川県立音楽堂、ANAクラウンプラザホテル金沢
  • Year and Date: 2015-10-16
• [Presentation] Target intracellular trafficking of FLT3-ITD and KIT D816V by Chlorpromazine shows promising preclinical activity against acute myeloid leukemia cells (2015)
  • Author(s): Rai S, Tanaka H, Matsumura I, et al.
  • Organizer: 第44回国際実験血液学会
  • Place of Presentation: 国立京都国際会館
  • Year and Date: 2015-09-17
  • Int'l Joint Research
• [Presentation] CALM plays a critical role for oncogenic activvity of RTK mutants and would be a promising therapeutiic target (2015)
  • Author(s): Tanaka H, Rai S, Matsumura I,et al.
  • Organizer: 第44回国際実験血液学会
  • Place of Presentation: 国立京都国際会館
  • Year and Date: 2015-09-17
  • Int'l Joint Research
• [Presentation] 同種造血幹細胞移植前処置におけるフルダラビン併用での静注ブスルファン使用量後方視的解析 (2015)
  • Author(s): 芹澤憲太郎、森田泰慶、谷口貴英、岩田 吉生、源周治、大山泰世、川内超矢、金井良高、賴晋也、平瀨主税、田中宏和、宮武淳一、辰巳陽一、芦田隆司、松村 到
  • Organizer: 第37回日本造血細胞移植学会総会
  • Place of Presentation: 神戸国際会議場・神戸ポートピアホテル
  • Year and Date: 2015-03-05 – 2015-03-07
• [Presentation] 同種造血幹細胞移植患者に対するフルコナゾールとイトラコナゾールによる侵襲製性アスペルギローシス予防効果の比較：D-index scoreを用いた後方視的解析 (2015)
  • Author(s): 宮武淳一、岩田吉生、谷口貴英、源周治、大山泰世、川内超矢、佐野圭吾、口分田貴裕、芹澤憲太郎、谷口貴英、賴晋也、金井良高、平瀨主税、森田泰慶、田中宏和、辰巳陽一、芦田隆司、松村 到
  • Organizer: 第37回日本造血細胞移植学会総会
  • Place of Presentation: 神戸国際会議場・神戸ポートピアホテル
  • Year and Date: 2015-03-05 – 2015-03-07
• [Presentation] 若年劇症型再生不良性貧血に対する 臍帯血移植に成功した一例 (2015)
  • Author(s): 口分田貴裕、岩田吉生、谷口貴英、源 周治、大山泰世、佐野圭吾、川内超矢、芹澤憲太郎、谷口康博、頼晋也、金井 良高、平瀬主税、森田泰慶、田中宏和、宮武淳一、辰巳陽一、芦田隆司、松村 到
  • Organizer: 第37回日本造血細胞移植学会総会
  • Place of Presentation: 神戸国際会議場・神戸ポートピアホテル
  • Year and Date: 2015-03-05 – 2015-03-07
• [Presentation] Analysis of conditioning regimen for ASCT with relapsed or refractory malignant lymphoma (2014)
  • Author(s): Kentaro Serizawa,Yasuyoshi Morita,Takahide Taniguchi,Yasuyo Oyama,Masaya Kawauchi,Takahiro Kumode,Yoshitaka kanai,Shikara Hirase,Hirokazu Tanaka,Jyunichi Miyatake,Youichi Tatsumi,Takashi Ashisda,Itaru Matsumura
  • Organizer: 第76回日本血液学会学術集会
  • Place of Presentation: 大阪・大阪国際会議場
  • Year and Date: 2014-10-31 – 2014-11-02
• [Presentation] A case of Mogamulizunab tertment for refractory ATLL to DLI following allo-SCT (2014)
  • Author(s): Takahide Taniguchi,kentaro Serizawa,Yasuyoshi Morita,Yasuyo Oyama,Masaya Kaawauchi,Takahiro Kumode,Yoshitaka Kanai,Chikara Hirase,Hirokazu Tanaka,Jyunichi Miyatake,Youichi Tatsumi,Takashi Ashida,Itaru Matsumura
  • Organizer: 第76回日本血液学会学術集会
  • Place of Presentation: 大阪・大阪国際会議場
  • Year and Date: 2014-10-31 – 2014-11-02
• [Presentation] ISS is a predictive factor of SCT effect for symptomatic myeloma patients under age 65 (2014)
  • Author(s): Hitomi Kaneko,Eiji Nakatani,Hirohiko Shibayama,Takae Kohara,Masayuki Kobayashi,Kazue Miyamoto,Maki Shindo,Shin-Ichi Fuchida,Hirokazu Tanaka,Junya Kuroda,Hideo Yagi,Satoru Kosugi,Toru Kida,Nobuhiko Uoshima,Yayoi Matsumura,Yuri Kamitsuji,Yoko Adachi,Kensuke Ohta,Kazuyoshi Ishii,Itaru Matsumura,Yuzuru Kanakura,et al.
  • Organizer: 第76回日本血液学会学術集会
  • Place of Presentation: 大阪・大阪国際会議場
  • Year and Date: 2014-10-31 – 2014-11-02
• [Presentation] The effects of consolisation and maintenance therapies for symptomatic MM patients after auto HSCT (2014)
  • Author(s): Hirohiko Shibayama,Eiji Nakatani Junya Kuroda,Shin-IchiFuchida,Hitomi kaneko,kensuke Ohta,Katae Kohara,Satoru kosugi,Yoko Adachi,Hideo Yagi,Masayuki Kobayashi,Kazue Miyamoto,Hirokazu Tanaka,Nobuhiko Uoshima,Toru Kida,Kazuyoshi Ishii,Yuri Kamitsuji,Tsuneyoshi Hamada,Itaru Matsumura,Yuzuru Kanakura,et al.
  • Organizer: 第76回日本血液学会学術集会
  • Place of Presentation: 大阪・大阪国際会議場
  • Year and Date: 2014-10-31 – 2014-11-02
• [Presentation] Leukemogenic FLT3-ITD and KIT D814V depend more in CALM function than their wild types to transmit growth/survival signals:Identification of CALM as a new therapeutic target (2014)
  • Author(s): Shinya Rai,Hirokazu Tanaka,Yasuhiro Taniguchi,Takahiro Shimada,Mai Suzuki,Akira Tanimura,Keiko Matsui,Toshio Watanabe,,Yuzuru Kanakura,Itaru Matsumura
  • Organizer: 第19回欧州血液学会
  • Place of Presentation: Italy・Milano
  • Year and Date: 2014-06-12 – 2014-06-15
• [Presentation] 当院における同種造血幹細胞移植時のダプトマイシンの有用性と安全性 (2014)
  • Author(s): 芹澤 憲太郎、森田 泰慶、江本正克、大山泰世、福井彩乃、井上宏昭、川内超矢、金井良高、平瀨主税、田中 宏和、嶋田 高広、宮武淳一、辰巳 陽一、芦田 隆司、松村 到
  • Organizer: 第36回日本造血細胞移植学会総会
  • Place of Presentation: 沖縄
• [Presentation] Retrospective analysis of 434 symptomatic myeloma cases registered in Kansai Myeloma Forum. (2013)
  • Author(s): Shibayama H, Ohta K, Tanaka H, Kohara T, Kosugi S, Kido T, Fuchida S, Miyamoto K, Shindo M, Kobayashi M, Hamada T, Nakatani E, Tudo M, Shimazaki C, Takaori A, Taniwaki M, Nomura S, Matsumura I, Kanakura Y, et al
  • Organizer: 第75回日本血液学会学術集会
  • Place of Presentation: ロイトン札幌・さっぽろ芸文館・札幌市教育文化会館
• [Presentation] Results of gemcitabine therapy for relapsed of refractory Non-Hodgkin's lymphoma in one institute. (2013)
  • Author(s): Serizawa K, Morita Y, Taniguchi Y, Kawauchi M, Eguchi G, Emoto M, Kanai Y, Rai S, Hirase C, Tanaka H, Shimada T, Tatsumi Y, Ashida T, Matsumura I.
  • Organizer: 第75回日本血液学会学術集会
  • Place of Presentation: ロイトン札幌・さっぽろ芸文館・札幌市教育文化会館
• [Presentation] Trib1 and Trib2 block myeloid differentiation by suppressing AKT phosphorylation. (2013)
  • Author(s): Kanai Y, Shimada T, Taniguchi Y, Rai S, Hirase C, Morita Y, Tanaka H, Miyatake J, Tatsumi Y, Ashida T, Matsumura I.
  • Organizer: 第75回日本血液学会学術集会
  • Place of Presentation: ロイトン札幌・さっぽろ芸文館・札幌市教育文化会館
• [Presentation] HDT with auto-PBSCT for myeloma un the new-agent era:A retrospective analysis of KMF registry (2013)
  • Author(s): Shimura Y，Tanaka H ,et al
  • Organizer: 第75回日本血液学会学術集会
  • Place of Presentation: ロイトン札幌・さっぽろ芸文館・札幌市教育文化会館
• [Presentation] CALM links cytokine signals to hematopoietic cell growth and survival by regulating intracellular trafficking of receptor tyrosine kinases (2013)
  • Author(s): Rai S, Tanaka H, Suzuki M, Tanimura A, Matsui K, Watanabe T ,Knakura Y, Matsumura I.
  • Organizer: 第18回 欧州血液学会
  • Place of Presentation: スウェーデン・ストックホルム
• [Presentation] Trib1 and Trib2 block myeloid differentiation by suppressing AKT phosphorylation (2013)
  • Author(s): Kanai Y, Shimada T, Tanaka H, Matsumura I.
  • Organizer: 第72回日本癌学会学術集会
  • Place of Presentation: パシフィコ横浜
• [Book] Annumal Review 血液 (2014)
  • Author(s): 平瀨主税、田中宏和、松村 到
  • Total Pages: 240
  • Publisher: 中外医学社
• [Book] EBM 血液疾患の治療 2015-2016 (2014)
  • Author(s): 平瀨主税、田中宏和、松村 到
  • Total Pages: 555
  • Publisher: 中外医学社
• [Book] ここまできた 白血病/MDS治療 (2013)
  • Author(s): 田中宏和・松村 到
  • Total Pages: 340
  • Publisher: 中山書店
• [Book] ここまできた 白血病/MDS治療 (2013)
  • Author(s): 田中宏和・平瀨主税・松村 到
  • Total Pages: 340
  • Publisher: 中山書店
• [Book] ここまできた 白血病/MDS治療 (2013)
  • Author(s): 平瀨主税・田中宏和・松村 到
  • Total Pages: 340
  • Publisher: 中山書店
• [Book] Annual Review 血液 (2013)
  • Author(s): 平瀨主税・田中宏和・松村 到
  • Total Pages: 240
  • Publisher: 中外医学社
• [Book] カラーテキスト 血液病学 (2013)
  • Author(s): 田中宏和・松村 到
  • Total Pages: 688
  • Publisher: 中外医学社