Development of a novel therapeutic method against acute megakaryoblastic leukemia by NOTCH agonists

• Project/Area Number: 15H04312
• Research Category: Grant-in-Aid for Scientific Research (B)
• Allocation Type: Single-year Grants
• Section: 一般
• Research Field: Tumor therapeutics
• Research Institution: Kumamoto University
• Principal Investigator: Osato Motomi 熊本大学, 国際先端医学研究機構, 特別招聘教授 (90314286)
• Co-Investigator(Kenkyū-buntansha): 横溝 智雅 熊本大学, 国際先端医学研究機構, 特定事業研究員 (80590314)
• Project Period (FY): 2015-04-01 – 2018-03-31
• Project Status: Completed (Fiscal Year 2017)
• Budget Amount: ¥16,770,000 (Direct Cost: ¥12,900,000、Indirect Cost: ¥3,870,000); Fiscal Year 2017: ¥4,810,000 (Direct Cost: ¥3,700,000、Indirect Cost: ¥1,110,000); Fiscal Year 2016: ¥5,850,000 (Direct Cost: ¥4,500,000、Indirect Cost: ¥1,350,000); Fiscal Year 2015: ¥6,110,000 (Direct Cost: ¥4,700,000、Indirect Cost: ¥1,410,000)
• Keywords: 分子標的治療 / 癌 / トランスレーショナルリサーチ / 内科 / 白血病

Outline of Final Research Achievements

The genetic lesions that drive acute megakaryoblastic leukemia (AMKL) have not been fully elucidated. To search for AMKL genes, an AMKL mouse model was developed employing retroviral insertional mutagenesis (RIM) on the mouse carrying alterations in two known AMKL genes, Gata-1 and Runx1. RIM screening identified genetic abrogations in Notch and JAK-STAT pathways. Extending these findings in mouse to human, we performed targeted deep sequencing in 34 AMKL patient samples and 8 AMKL cell lines, and detected genetic mutations in Notch and JAK-STAT pathways. NOTCH activator, but not inhibitor, and JAK inhibitor significantly suppressed AMKL cell proliferation by inducing apoptosis individually as a single agent and synergistically as a combination therapy. Notably, this Notch activation is induced in a ligand-independent manner, revealing a novel mechanism that holds a potential of therapeutic application for AMKL.

Research Products

• [Int'l Joint Research] National University of Singapore(Singapore)
• [Int'l Joint Research] University of Otago(New Zealand)
• [Int'l Joint Research] National University of Singapore(Singapore)
• [Int'l Joint Research] National University of Singapore(Singapore)
• [Int'l Joint Research] University of Otago(New Zealand)
• [Journal Article] A DNA Contact Map for the Mouse Runx1 Gene Identifies Novel Haematopoietic Enhancers (2017)
  • Author(s): Marsman Judith、Thomas Amarni、Osato Motomi、O’Sullivan Justin M.、Horsfield Julia A.
  • Journal Title: Scientific Reports Volume: 7 Issue: 1 Pages: 13347-13347
  • DOI: 10.1038/s41598-017-13748-8
  • Peer Reviewed / Open Access / Int'l Joint Research
• [Journal Article] In?Vivo Generation of Engraftable Murine Hematopoietic Stem Cells by Gfi1b, c-Fos , and Gata2 Overexpression within Teratoma (2017)
  • Author(s): Tsukada Masao、Ota Yasunori、Wilkinson Adam C.、Becker Hans J.、Osato Motomi、Nakauchi Hiromitsu、Yamazaki Satoshi
  • Journal Title: Stem Cell Reports Volume: 9 Issue: 4 Pages: 1024-1033
  • DOI: 10.1016/j.stemcr.2017.08.010
  • Peer Reviewed / Open Access / Int'l Joint Research
• [Journal Article] Ikk2 regulates cytokinesis during vertebrate development (2017)
  • Author(s): Shen Hongyuan、Shin Eun Myoung、Lee Serene、Mathavan Sinnakaruppan、Koh Hiromi、Osato Motomi、Choi Hyungwon、Tergaonkar Vinay、Korzh Vladimir
  • Journal Title: Scientific Reports Volume: 7 Issue: 1 Pages: 8094-8094
  • DOI: 10.1038/s41598-017-06904-7
  • Peer Reviewed / Int'l Joint Research
• [Journal Article] Runx Family Genes in Tissue Stem Cell Dynamics. (2017)
  • Author(s): Wang CQ, Mok MM, Yokomizo T, Tergaonkar V, Osato M.
  • Journal Title: Adv Exp Med Biol. Volume: 962 Pages: 117-138
  • DOI: 10.1007/978-981-10-3233-2_9
  • ISBN: 9789811032318, 9789811032332
  • Peer Reviewed / Int'l Joint Research / Acknowledgement Compliant
• [Journal Article] RUNX3 is oncogenic in natural killer/T-cell lymphoma and is transcriptionally regulated by MYC. (2016)
  • Author(s): Selvarajan V, Osato M, Nah GS, Yan J, Chung TH, Voon DC, Ito Y, Ham MF, Salto-Tellez M, Shimizu N, Choo SN, Fan S, Chng WJ, Ng SB.
  • Journal Title: Leukemia Volume: 印刷中 Issue: 10 Pages: 2219-2227
  • DOI: 10.1038/leu.2017.40
  • Peer Reviewed / Open Access / Int'l Joint Research
• [Journal Article] Aberrant activation of the GIMAP enhancer by oncogenic transcription factors in T-cell acute lymphoblastic leukemia. (2016)
  • Author(s): Liau WS, Tan SH, Ngoc PC, Wang CQ, Tergaonkar V, Feng H, Gong Z, Osato M, Look AT, Sanda T.
  • Journal Title: Leukemia Volume: 印刷中 Issue: 8 Pages: 1798-1807
  • DOI: 10.1038/leu.2016.392
  • Peer Reviewed / Open Access / Int'l Joint Research
• [Journal Article] LIN28B Activation by PRL-3 Promotes Leukemogenesis and a Stem Cell-like Transcriptional Program in AML. (2016)
  • Author(s): Zhou J, Chan ZL, Bi C, Lu X, Chong PS, Chooi JY, Cheong LL, Liu SC, Ching YQ, Zhou Y, Osato M, Tan TZ, Ng CH, Ng SB, Wang S, Zeng Q, Chng WJ.
  • Journal Title: Mol Cancer Res Volume: 15 Issue: 3 Pages: 294-303
  • DOI: 10.1158/1541-7786.mcr-16-0275-t
  • Peer Reviewed / Open Access / Int'l Joint Research
• [Journal Article] Activation of EVI1 transcription by the LEF1/β-catenin complex with p53-alteration in myeloid blast crisis of chronic myeloid leukemia. (2016)
  • Author(s): Manachai N, Saito Y, Nakahata S, Bahirvani AG, Osato M, Morishita K.
  • Journal Title: Biochem Biophys Res Commun Volume: 482 Issue: 4 Pages: 994-1000
  • DOI: 10.1016/j.bbrc.2016.11.146
  • Peer Reviewed / Int'l Joint Research
• [Journal Article] Identification of Stem Cells in the Epithelium of the Stomach Corpus and Antrum of Mice. (2016)
  • Author(s): Matsuo J, Kimura S, Yamamura A, Koh CP, Hossain MZ, Heng DL, Kohu K, Voon DC, Hiai H, Unno M, So JB, Zhu F, Srivastava S, Teh M, Yeoh KG, Osato M, Ito Y.
  • Journal Title: Gastroenterology Volume: 152 Issue: 1 Pages: 218-231
  • DOI: 10.1053/j.gastro.2016.09.018
  • Peer Reviewed / Open Access / Int'l Joint Research
• [Journal Article] Lack of Phenotypical and Morphological Evidences of Endothelial to Hematopoietic Transition in the Murine Embryonic Head during Hematopoietic Stem Cell Emergence. (2016)
  • Author(s): Iizuka K, Yokomizo T, Watanabe N, Tanaka Y, Osato M, Takaku T, Komatsu N.
  • Journal Title: PLoS One Volume: 11 Issue: 5 Pages: e0156427-e0156427
  • DOI: 10.1371/journal.pone.0156427
  • Peer Reviewed / Open Access
• [Journal Article] Cyclin A2 regulates erythrocyte morphology and numbers. (2016)
  • Author(s): Jayapal SR, Ang HY, Wang CQ, Bisteau X, Caldez MJ, Xuan GX, Yu W, Tergaonkar V, Osato M, Lim B, Kaldis P.
  • Journal Title: Cell Cycle Volume: 15 Issue: 22 Pages: 3070-3081
  • DOI: 10.1080/15384101.2016.1234546
  • Peer Reviewed / Int'l Joint Research
• [Journal Article] Functional and molecular characterization of mouse Gata2-independent hematopoietic progenitors. (2016)
  • Author(s): Kaimakis P, de Pater E, Eich C, Solaimani Kartalaei P, Kauts ML, Vink CS, van der Linden R, Jaegle M, Yokomizo T, Meijer D, Dzierzak E.
  • Journal Title: Blood Volume: 127 Issue: 11 Pages: 1426-1437
  • DOI: 10.1182/blood-2015-10-673749
  • Peer Reviewed / Int'l Joint Research
• [Journal Article] RUNX1 haploinsufficiency results in granulocyte colony-stimulating factor hypersensitivity. (2016)
  • Author(s): Chin DW, Sakurai M, Nah GS, Du L, Jacob B, Yokomizo T, Matsumura T, Suda T, Huang G, Fu XY, Ito Y, Nakajima H, Osato M.
  • Journal Title: Blood Cancer J. Volume: 6 Issue: 1 Pages: e379-e379
  • DOI: 10.1038/bcj.2015.105
  • Peer Reviewed / Open Access / Int'l Joint Research
• [Journal Article] The artificial loss of Runx1 reduces the expression of quiescence-associated transcription factors in CD4(+) T lymphocytes. (2015)
  • Author(s): Wong WF, Kohu K, Nagashima T, Funayama R, Matsumoto M, Movahed E, Tan GM, Yeow TC, Looi CY, Kurokawa M, Osato M, Igarashi K, Nakayama K, Satake M.
  • Journal Title: Mol Immunol. Volume: 68 Issue: 2 Pages: 223-33
  • DOI: 10.1016/j.molimm.2015.08.012
  • Peer Reviewed / Open Access / Int'l Joint Research
• [Journal Article] Mouse models for core binding factor leukemia. (2015)
  • Author(s): Chin DW, Watanabe-Okochi N, Wang CQ, Tergaonkar V, Osato M.
  • Journal Title: Leukemia Volume: 29 Issue: 10 Pages: 1970-80
  • DOI: 10.1038/leu.2015.181
  • Peer Reviewed / Open Access / Int'l Joint Research
• [Journal Article] MYC regulates the core pre-mRNA splicing machinery as an essential step in lymphomagenesis. (2015)
  • Author(s): Koh CM, Bezzi M, Low DH, Ang WX, Teo SX, Gay FP, Al-Haddawi M, Tan SY, Osato M, Sabò A, Amati B, Wee KB, Guccione E.
  • Journal Title: Nature Volume: 523 Issue: 7558 Pages: 96-100
  • DOI: 10.1038/nature14351
  • Peer Reviewed / Int'l Joint Research
• [Journal Article] DUSP10 regulates intestinal epithelial cell growth and colorectal tumorigenesis. (2015)
  • Author(s): Png CW, Weerasooriya M, Guo J, James SJ, Poh HM, Osato M, Flavell RA, Dong C, Yang H, Zhang Y.
  • Journal Title: Oncogene Volume: 35 Issue: 2 Pages: 206-17
  • DOI: 10.1038/onc.2015.74
  • Peer Reviewed / Open Access / Int'l Joint Research
• [Journal Article] Hematopoiesis specific loss of Cdk2 and Cdk4 results in increased erythrocyte size and delayed platelet recovery following stress. (2015)
  • Author(s): Jayapal SR, Wang CQ, Bisteau X, Caldez MJ, Lim S, Tergaonkar V, Osato M, Kaldis P.
  • Journal Title: Haematologica Volume: 100 Pages: 431-8
  • Peer Reviewed / Open Access / Int'l Joint Research
• [Journal Article] Bimodal Influence of Vitamin D in Host Response to Systemic Candida Infection-Vitamin D Dose Matters. (2015)
  • Author(s): Lim JH, Ravikumar S, Wang YM, Thamboo TP, Ong L, Chen J, Goh JG, Tay SH, Chengchen L, Win MS, Leong W, Lau T, Foo R, Mirza H, Tan KS, Sethi S, Khoo AL, Chng WJ, Osato M, Netea MG, Wang Y, Chai LY.
  • Journal Title: J Infect Dis Volume: 212 Issue: 4 Pages: 635-44
  • DOI: 10.1093/infdis/jiv033
  • Peer Reviewed / Open Access / Int'l Joint Research
• [Journal Article] Hematopoietic stem cell enhancer: a powerful tool in stem cell biology. (2015)
  • Author(s): Koh CP, Ng CE, Nah GS, Wang CQ, Tergaonkar V, Matsumura T, Yokomizo T, Suda T, Osato M.
  • Journal Title: Histol Histopathol Volume: 30 Pages: 661-72
  • Peer Reviewed / Open Access / Int'l Joint Research
• [Journal Article] Whole-transcriptome analysis of endothelial to hematopoietic stem cell transition reveals a requirement for Gpr56 in HSC generation. (2015)
  • Author(s): Solaimani Kartalaei P, Yamada-Inagawa T, Vink CS, de Pater E, van der Linden R, Marks-Bluth J, van der Sloot A, van den Hout M, Yokomizo T, van Schaick-Solernó ML, Delwel R, Pimanda JE, van IJcken WF, Dzierzak E.
  • Journal Title: J Exp Med Volume: 212 Issue: 1 Pages: 93-106
  • DOI: 10.1084/jem.20140767
  • Peer Reviewed / Int'l Joint Research
• [Journal Article] Cbfb deficiency results in differentiation blocks and stem/progenitor cell expansion in hematopoiesis. (2014)
  • Author(s): Wang CQ, Chin DW, Chooi JY, Wee Joo C, Taniuchi I, Tergaonkar V, Osato M.
  • Journal Title: Leukemia Volume: 29 Issue: 3 Pages: 753-7
  • DOI: 10.1038/leu.2014.316
  • Peer Reviewed / Open Access
• [Presentation] 急性巨核芽球性白血病に対する新規治療法 (2018)
  • Author(s): 大里元美
  • Organizer: 第22回造血器腫瘍研究会
• [Presentation] Enhancer for Runx1, eR1: a powerful tool in stem cell and cancer biology (2018)
  • Author(s): 大里元美
  • Organizer: 平成29年度先端モデル動物支援プラットフォーム成果発表会
• [Presentation] Hlf marks nascent HSCs, but not EMPs. (2018)
  • Author(s): Osato M
  • Organizer: JSPS & NUS Joint 2nd Symposium
  • Int'l Joint Research
• [Presentation] RUNX3エンハンサーeR3による腸上皮細胞間リンパ球の抗腫瘍効果制御機構 (2017)
  • Author(s): Osato M
  • Organizer: Cancer Research Institute of Kanazawa University symposium
  • Place of Presentation: Kanazawa, Japan
  • Year and Date: 2017-02-14
  • Invited
• [Presentation] A novel treatment and prevention for acute megakaryoblastic leukemia in Singapore and Malaysia (2017)
  • Author(s): Osato M
  • Organizer: AIMST International Conference on Non-Communicable Diseases
  • Int'l Joint Research / Invited
• [Presentation] スフィンゴシン１リン酸S1Pによるリガンド非依存性NOTCH活性化を介した白血病治療 (2017)
  • Author(s): 大里元美
  • Organizer: 第12回 スフィンゴテラピィ研究会
  • Invited
• [Presentation] Enancer for Runx1, eR1: a powerful tool in stem cell and cancer biology (2017)
  • Author(s): Osato M
  • Organizer: 21st International RUNX Conference
  • Int'l Joint Research
• [Presentation] RUNX2 superenhancer-driven MYC activation causes blastic plasmacytoid dendritic cell neoplasm. (2017)
  • Author(s): 大里元美
  • Organizer: 第21回造血器腫瘍研究会
• [Presentation] Enhancer for Runx1, eR1: a powerful tool in stem cell and cancer biology (2016)
  • Author(s): Osato M
  • Organizer: 39th Annual Mtg of Molecular Biology Society of Japan
  • Place of Presentation: Yokohama, Japan
  • Year and Date: 2016-11-30
  • Int'l Joint Research / Invited
• [Presentation] Enhancer for Runx1, eR1: a powerful tool in stem cell and cancer biology (2016)
  • Author(s): Osato M
  • Organizer: 14th Stem Cell Res Symposium
  • Place of Presentation: Awaji, Japan
  • Year and Date: 2016-05-20
  • Int'l Joint Research
• [Presentation] Enhancer for Runx1, eR1: a powerful tool in stem cell biology (2016)
  • Author(s): Osato M
  • Organizer: JSPS-NUS Joint Symposium
  • Place of Presentation: Singapore (Singapore)
  • Year and Date: 2016-01-14
  • Int'l Joint Research
• [Presentation] Whole-mount three-dimensional analysis of hematopoietic development in the mouse embryonic head (2016)
  • Author(s): Yokomizo T, Iizuka K, Osato M, Takaku T, Komatsu N
  • Organizer: JSPS-NUS Joint Symposium
  • Place of Presentation: Singapore (Singapore)
  • Year and Date: 2016-01-14
  • Int'l Joint Research
• [Presentation] Highly efficient Runx1 enhancer eR1-mediated genetic engineering for fetal, child and adult hematopoietic stem cells (2015)
  • Author(s): Osato M
  • Organizer: 14th Asian Conference on Transcription
  • Place of Presentation: Singapore (Singapore)
  • Year and Date: 2015-12-03
  • Int'l Joint Research
• [Presentation] Enhancer for Runx1, eR1: a powerful tool in stem cell and cancer biology (2015)
  • Author(s): Osato M
  • Organizer: Frontiers in Cancer Science 2015
  • Place of Presentation: Singapore (Singapore)
  • Year and Date: 2015-11-02
  • Int'l Joint Research / Invited
• [Presentation] An Upstream RUNX3 Enhancer Regulates the Development of Gut-Associated Anti-Tumorigenic CD8+CD103+ Cytotoxic T Lymphocytes (2015)
  • Author(s): Osato M
  • Organizer: 20th Runx meeting
  • Place of Presentation: Rehovot(Israel)
  • Year and Date: 2015-10-18
  • Int'l Joint Research
• [Presentation] Intraepithelial Lymphocytes against Gastrointestinal Cancer (2015)
  • Author(s): Osato M
  • Organizer: Singapore Gastric Cancer Consortium’s 8th Annual Scientific Meeting
  • Place of Presentation: Singapore (Singapore)
  • Year and Date: 2015-07-22
  • Int'l Joint Research / Invited
• [Presentation] Highly efficient Runx1 enhancer eR1-mediated genetic engineering for fetal and adult hematopoietic stem cells (2015)
  • Author(s): Osato M, Koh CP, Yokomizo T
  • Organizer: 13th Stem Cell Research Symposium
  • Place of Presentation: University of Tokyo (Tokyo, Japan)
  • Year and Date: 2015-05-29
  • Int'l Joint Research
• [Presentation] Disruption of Runx1 and Runx3 Leads to Bone Marrow Failure and Leukemia Predisposition due to Transcriptional and DNA Repair Defects. (2015)
  • Author(s): Osato M
  • Organizer: 6th JSH International Symposium
  • Place of Presentation: Karuizawa Prince Hotel (Nagano, Japan)
  • Year and Date: 2015-05-22
  • Int'l Joint Research
• [Remarks] Identification of Gastric Stem Cells in Mice
  • URL: http://ircms.kumamoto-u.ac.jp/publications/2017/01/identification-of-stem-cells-in-the-epithelium-of-the-stomach-corpus-and-antrum-of-mice.html
• [Remarks] Mouse models for core binding factor leukemia
  • URL: http://ircms.kumamoto-u.ac.jp/publications/2015/07/mouse-models-for-core-binding-factor-leukemia.html
• [Remarks] Cbfb knockout mice
  • URL: http://ircms.kumamoto-u.ac.jp/publications/2015/03/cbfb-knockout-mice.html
• [Remarks] Hematopoietic stem cell enhancer
  • URL: http://ircms.kumamoto-u.ac.jp/publications/2015/01/hematopoietic-stem-cell-enhancer.html
• [Remarks] Stem Cells in the Epithelium of the Stomach