Targeting cancer stem cells in chronic myeloid neoplasms

• Project/Area Number: 26461424
• Research Category: Grant-in-Aid for Scientific Research (C)
• Allocation Type: Multi-year Fund
• Section: 一般
• Research Field: Hematology
• Research Institution: Kyushu University
• Principal Investigator: TAKENAKA KATSUTO 九州大学, 大学病院, 講師 (30301295)
• Project Period (FY): 2014-04-01 – 2017-03-31
• Project Status: Completed (Fiscal Year 2016)
• Budget Amount: ¥4,810,000 (Direct Cost: ¥3,700,000、Indirect Cost: ¥1,110,000); Fiscal Year 2016: ¥1,560,000 (Direct Cost: ¥1,200,000、Indirect Cost: ¥360,000); Fiscal Year 2015: ¥1,690,000 (Direct Cost: ¥1,300,000、Indirect Cost: ¥390,000); Fiscal Year 2014: ¥1,560,000 (Direct Cost: ¥1,200,000、Indirect Cost: ¥360,000)
• Keywords: 骨髄増殖性腫瘍 / 骨髄異形成症候群 / がん幹細胞 / 免疫不全マウス / SIRPA / Kit変異 / 幹細胞アッセイシステム / 異種移植モデル

Outline of Final Research Achievements

Cancer stem cells (CSCs) are therapeutic targets and must be eliminated to cure the patients. Howerver ,those cells have not been found yet in MDS/MPN. Immunodeficient mice are widely used to reconstitute human normal hematopoiesis and acute leukemia. Howerever, in these models, significant reconstitution of human erythroid and megakaryocyte lineages has been difficult to achieve. Here, we show that introduction of homozygous KitWv mutation (K) into the C57BL/6.Rag2(null)Il2rg(null) mice with NOD-Sirpa (BRGS) strongly promoted human multilineage reconstitution. The new BRGSK mice showed significantly higher levels of human cell chimerism and myeloid reconstitution for a long-term, as compared to BRGS mice. Strikingly, BRGSK mice displayed robust reconstitution of human erythropoiesis and thrombopoiesis with terminal maturation in the bone marrow.This new xenograft model should be a strong tool to study human hematopoiesis including erythropoiesis and thrombopoiesis.

Research Products

• [Journal Article] Clinical features and outcomes of patients with primary myelofibrosis in Japan: report of a 17-year nationwide survey by the Idiopathic Disorders of Hematopoietic Organs Research Committee of Japan. (2017)
  • Author(s): Takenaka K, Shimoda K, Uchida N, Shimomura T, Nagafuji K, Kondo T, Shibayama H, Mori T, Usuki K, Azuma T, Tsutsumi Y, Tanaka J, Dairaku H, Matsuo K, Ozawa K, Kurokawa M, Arai S, Akashi K.
  • Journal Title: Int J Henatol Volume: 105 Issue: 1 Pages: 59-69
  • DOI: 10.1007/s12185-016-2102-3
  • Peer Reviewed / Acknowledgement Compliant
• [Journal Article] Enhanced Reconstitution of Human Erythropoiesis and Thrombopoiesis in an Immunodeficient Mouse Model with Kit(Wv) Mutations. (2016)
  • Author(s): A. Yurino, K. Takenaka, T. Yamauchi, T. Nunomura, Y. Uehara, F. Jinnouchi, K. Miyawaki, Y. Kikushige, K. Kato, T. Miyamoto, H. Iwasaki, Y. Kunisaki, *K. Akashi
  • Journal Title: Stem Cell Reports Volume: 7 Issue: 3 Pages: 425-438
  • DOI: 10.1016/j.stemcr.2016.07.002
  • Peer Reviewed / Open Access / Acknowledgement Compliant
• [Journal Article] Calreticulin mutation does not contribute to disease progression in essential thrombocythemia by inhibiting phagocytosis. (2016)
  • Author(s): S. Daitoku, K. Takenaka, T. Yamauchi, A. Yurino, F. Jinnouchi, T. Nunomura, T. Eto, T. Kamimura, M. Higuchi, N. Harada, N. Saito, T. Miyamoto, H. Iwasaki, *K. Akashi
  • Journal Title: Exp Hematol Volume: 44 Issue: 9 Pages: 817-825
  • DOI: 10.1016/j.exphem.2016.05.001
  • Peer Reviewed
• [Journal Article] Splenic irradiation provides transient palliation for symptomatic splenomegaly associated with primary myelofibrosis: a report on 14 patients. (2015)
  • Author(s): Kitanaka A, Takenaka K, Shide K, Miyamoto T, Kondo T, Ozawa K, Kurokawa M, Akashi K, Shimoda K.
  • Journal Title: Int J Hematol Volume: 103 Issue: 4 Pages: 423-428
  • DOI: 10.1007/s12185-016-1940-3
  • Peer Reviewed / Open Access / Int'l Joint Research
• [Journal Article] A TIM-3/Gal-9 Autocrine Stimulatory Loop Drives Self-Renewal of Human Myeloid Leukemia Stem Cells and Leukemic Progression. (2015)
  • Author(s): Kikushige Y, Miyamoto T, Yuda J, Jabbarzadeh-Tabrizi S, Shima T, Takayanagi S, Niiro H, Yurino A, Miyawaki K, Takenaka K, Iwasaki H, Akashi K
  • Journal Title: Cell Stem Cell. Volume: 17 Issue: 3 Pages: 341-352
  • DOI: 10.1016/j.stem.2015.07.011
  • Peer Reviewed / Int'l Joint Research
• [Journal Article] A multinational, open-label, phase 2 study of ruxolitinib in Asian patients with myelofibrosis: Japanese subset analysis. (2015)
  • Author(s): Oritani K, Okamoto S, Tauchi T, Saito S, Ohishi K, Handa H, Takenaka K, Gopalakrishna P, Amagasaki T, Ito K, Akashi K.
  • Journal Title: Int J Hematol Volume: 101 Issue: 3 Pages: 295-304
  • DOI: 10.1007/s12185-015-1746-8
  • Peer Reviewed / Int'l Joint Research
• [Journal Article] CD41 marks the initial myelo-erythroid lineage specification in adult mouse hematopoiesis: redefinition of murine common myeloid progenitor. (2015)
  • Author(s): Miyawaki K, Arinobu Y, Iwasaki H, Kohno K, Tsuzuki H, Iino T, Shima T, Kikushige Y, Takenaka K, Miyamoto T, Akashi K.
  • Journal Title: Stem Cells Volume: 33 Issue: 3 Pages: 976-87
  • DOI: 10.1002/stem.1906
  • Peer Reviewed
• [Journal Article] Efficacy and safety of ruxolitinib in Asian patients with myelofibrosis. (2015)
  • Author(s): Jung CW, Shih LY, Xiao Z, Jie J, Hou HA, Du X, Wang MC, Park S, Eom KS, Oritani K, Okamoto S, Tauchi T, Kim JS, Zhou D, Saito S, Li J, Handa H, Jianyong L, Ohishi K, Hou M, Depei W, Takenaka K, Liu T, Hu Y, Amagasaki T, Ito K, Gopalakrishna P, Akashi K.
  • Journal Title: Leuk Lymphoma Volume: 56 Issue: 7 Pages: 2067-2074
  • DOI: 10.3109/10428194.2014.969260
  • Peer Reviewed / Int'l Joint Research
• [Journal Article] The ordered acquisition of Class II and Class I mutations directs formation of human t(8;21) acute myelogenous leukemia stem cell. (2014)
  • Author(s): Shima T, Miyamoto T, Kikushige Y, Yuda J, Tochigi T, Yoshimoto G, Kato K, Takenaka K, Iwasaki H, Mizuno S, Goto N, Akashi K.
  • Journal Title: Exp. Hematol. Volume: 42 Issue: 11 Pages: 955-65
  • DOI: 10.1016/j.exphem.2014.07.267
  • Peer Reviewed / Open Access
• [Presentation] Introduction of Macrophage Tolerance By Human SIRPA Knock-in Enhances Peripheral Reconstitution of Human Hematopoiesis in Xenotransplantation Model (2016)
  • Author(s): Jinnnouchi F, Takenaka K, Iwamoto C, Yamauchi T, Yurino A, Nunomura T, Kikushige Y, Kato K, Miyamoto T, Akashi K
  • Organizer: the 58th of annual meeting of American Society of Hematology
  • Place of Presentation: San Diego, CA
  • Year and Date: 2016-12-03
  • Int'l Joint Research
• [Presentation] Fibrotic tissues in human primary myelofibrosis with JAK2V617F are developed clonally from malignant hematopoietic stem cells (2015)
  • Author(s): Katsuto Takenaka
  • Organizer: The 6th JSH International Symposium 2015
  • Place of Presentation: Karuizawa, Japan
  • Year and Date: 2015-05-23
  • Int'l Joint Research / Invited