The analysis of leukemia stem cell using iPS cell technology

• Project/Area Number: 23591369
• Research Category: Grant-in-Aid for Scientific Research (C)
• Allocation Type: Multi-year Fund
• Section: 一般
• Research Field: Hematology
• Research Institution: Kansai Medical University (2013); The University of Tokyo (2011-2012)
• Principal Investigator: KUMANO keiki 関西医科大学, 医学部, 准教授 (90396721)
• Co-Investigator(Renkei-kenkyūsha): KAMIKUBO Yasuhiko 京都大学, 医学部, 准教授 (60548527)
• Project Period (FY): 2011 – 2013
• Project Status: Completed (Fiscal Year 2013)
• Budget Amount: ¥5,200,000 (Direct Cost: ¥4,000,000、Indirect Cost: ¥1,200,000); Fiscal Year 2013: ¥1,040,000 (Direct Cost: ¥800,000、Indirect Cost: ¥240,000); Fiscal Year 2012: ¥1,950,000 (Direct Cost: ¥1,500,000、Indirect Cost: ¥450,000); Fiscal Year 2011: ¥2,210,000 (Direct Cost: ¥1,700,000、Indirect Cost: ¥510,000)
• Keywords: iPS細胞 / 白血病幹細胞 / iPS cells

Research Abstract

Induced pluripotent stem cells (iPSCs) can be generated by the expression of defined transcription factors not only from normal tissue, but also from malignant cells. Bone marrow cells from a chronic myelogenous leukemia (CML), myelofibrosis (MF), essential thrombocythemia (ET) patient were reprogrammed by introducing the transcription factors Oct3/4, Sox2, KLF4, and c-myc. Then we differentiated them into hematopoietic progenitors. They showed the hematopoietic marker CD45 and immature marker CD34. CML derived hematopoietic cells recovered the sensitivity to imatinib, which recapitulated the feature of initial CML disease. mRNA levels of IL-8, one of candidate cytokines related to the pathogenesis of myelofibrosis, was expressed elevated predominantly in megakaryocytes derived from MF-iPSCs. Thus, this system can act as a new platform for the elucidation of the disease mechanism and drug screening.

Research Products

• [Journal Article] Generation of induced pluripotent stem cells derived from primary and secondary myelofibrosis patient samples (2014)
  • Author(s): Hosoi M, Kumano K, Taoka K, Arai S, Kataoka K, Ueda K, Kamikubo Y, Takayama N, Otsu M, Eto K, Nakauchi H, Kurokawa M
  • Journal Title: Exp Hematol Volume: (in press) Issue: 9 Pages: 816-25
  • DOI: 10.1016/j.exphem.2014.03.010
  • Peer Reviewed / Open Access
• [Journal Article] The IL-2/CD25 Axis Maintains Distinct Subsets of Chronic M yeloid Leukemia-initiating Cells. (2014)
  • Author(s): Kobayashi CI, Takubo K, Kobayashi H, Nakamura-Ishizu A, Honda H, Kataoka K, Kumano K, Akiyama H, Sudo T, Kurokawa M, Suda T.
  • Journal Title: Blood Volume: 123 Issue: 16 Pages: 2540-2549
  • DOI: 10.1182/blood-2013-07-517847
  • Peer Reviewed / Open Access
• [Journal Article] Positive feedback between NF-κB and TNF-α promotes leukemia-initiating cell capacity. (2014)
  • Author(s): Kagoya Y, Yoshimi A, Kataoka K, Nakagawa M, Kumano K, Arai S, Kobayashi H, Saito T, Iwakura Y, Kurokawa M.
  • Journal Title: J Clin Invest. Volume: 124 Issue: 2 Pages: 528-542
  • DOI: 10.1172/jci68101
  • Peer Reviewed
• [Journal Article] Generation of iPS cells from normal and malignant hematopoietic cells. (2013)
  • Author(s): Kumano K, Arai S, Kurokawa M.
  • Journal Title: Int J Hematol. Volume: 98 Issue: 2 Pages: 145-182
  • DOI: 10.1007/s12185-013-1385-x
  • NAID: 10031194728
  • Peer Reviewed
• [Journal Article] The significance of free light chain measurements in the diagnosis of myelomatous pleural effusion. (2013)
  • Author(s): Tsukamoto A, Yoshiki Y, Yamazaki S, Kumano K, Nakamura F, Kurokawa M.
  • Journal Title: Ann Hematol. Volume: 93 Issue: 3 Pages: 507-508
  • DOI: 10.1007/s00277-013-1818-x
  • Peer Reviewed
• [Journal Article] The shortest isoform of C/EBPβ, Liver inhibitory protein (LIP) , collaborates with Evi1 to induce AML in a mouse BMT model (2013)
  • Author(s): Okochi, N., Yoshimi, A., Sato, T., Ikeda, T., Kumano, K., Taoka, K., Sato, Y., Shinohara, A., Tsuruta, A., Masuda, A., Yokota, H., Yatomi, Y., Takahashi, K., Kitaura, J., Kitamura, T. and Kurokawa, M
  • Journal Title: Blood Volume: 121 Issue: 20 Pages: 4142-4155
  • DOI: 10.1182/blood-2011-07-368654
  • NAID: 10031196292
  • Peer Reviewed
• [Journal Article] Generation of induced pluripotent stem cells from primary chronic myelogenous leukemia (2012)
  • Author(s): Keiki Kumano
  • Journal Title: BLOOD Volume: 119 Issue: 26 Pages: 6234-6242
  • DOI: 10.1182/blood-2011-07-367441
  • Peer Reviewed
• [Journal Article] Multiple phosphorylation sites are important for RUNX1 activity in early hematopoiesis and T-cell differentiation. (2012)
  • Author(s): Yoshimi M, Goyama S, Kawazu M, Nakagawa M, Ichikawa M, Imai Y, Kumano K, Asai T, Mulloy JC, Kraft AS, Takahashi T, Shirafuji N, Kurokawa M.
  • Journal Title: Eur J Immunol. Volume: 42 Issue: 4 Pages: 1044-1050
  • DOI: 10.1002/eji.201040746
  • Peer Reviewed
• [Journal Article] ヒトCML検体からのiPS細胞の作製と解析 (2012)
  • Author(s): 熊野恵城、黒川峰夫
  • Journal Title: 血液内科 Volume: 65 Pages: 710-716
  • NAID: 40019515733
• [Journal Article] The effect of iron overload and chelation on erythroid differentiation (2011)
  • Author(s): Taoka K, Kumano K, Nakamura F, Hosoi M, Goyama S, Imai Y, Hangaishi A, Kurokawa M
  • Journal Title: International Journal of Hematology Volume: 95 Issue: 2 Pages: 149-159
  • DOI: 10.1007/s12185-011-0988-3
  • NAID: 10030267276
  • Peer Reviewed
• [Journal Article] Outcome of medium-dose VP-16/CY/TBI superior to CY/TBI as a conditioning regimen for allogeneic stem cell transplantation in adult patients with acute lymphoblastic leukemia (2011)
  • Author(s): Shigematsu A, et al
  • Journal Title: International Journal of Hematology Volume: 94(5) Issue: 5 Pages: 463-471
  • DOI: 10.1007/s12185-011-0944-2
  • Peer Reviewed
• [Journal Article] Evi1 is essential for hematopoietic stem cell self-renewal, and its expression marks hematopoietic cells with long-term multilineage repopulating activity (2011)
  • Author(s): Keisuke Kataoka
  • Journal Title: The Journal of Experimental Medicine Volume: 208 Issue: 12 Pages: 2403-2416
  • DOI: 10.1084/jem.20110447
  • Peer Reviewed
• [Journal Article] AML1/RUNX1 functions as a cytoplasmic attenuator of NF-κB signaling in the repression of myeloid tumors (2011)
  • Author(s): Masahiro Nakagawa
  • Journal Title: Blood Volume: 118 Issue: 25 Pages: 6626-6637
  • DOI: 10.1182/blood-2010-12-326710
  • Peer Reviewed
• [Journal Article] Loss of AML1/Runx1 accelerates the development of MLL-ENL leukemia through downregulation of p19ARF (2011)
  • Author(s): 黒川峰夫, 他
  • Journal Title: Blood Volume: 118 Issue: 9 Pages: 2541-2550
  • DOI: 10.1182/blood-2010-10-315440
  • Peer Reviewed
• [Journal Article] Notch2 signaling is required for proper mast cell distribution and mucosal immunity in the intestine (2011)
  • Author(s): Sakata-Yanagimoto M, Sakai T, Miyake Y, Saito T, Maruyama H, Morishita Y, Nakagami-Yamaguchi E, Kumano K, Yagita H, Fukayama M, Ogawa S, Kurokawa M, Yasutomo K, Chiba S
  • Journal Title: Blood Volume: 117 Issue: 1 Pages: 128-134
  • DOI: 10.1182/blood-2010-07-289611
  • NAID: 120007137632
  • Peer Reviewed
• [Presentation] Generation of induced pluripotent stem cells from primary hematological malignancies (2012)
  • Author(s): Keiki Kumano, Shunya Arai, Masataka Hosoi, Kazuki Taoka, Koki Ueda, Kumi Nakazaki, Yasuhiko Kamikubo, Mineo Kurokawa
  • Organizer: International Society for Stem cell Research (ISSCR) annual meeting
  • Place of Presentation: Yokohama
  • Year and Date: 2012-06-12
• [Presentation] Generation of induced pluripotent stem cells from primary hematological malignancies. (2012)
  • Author(s): Keiki Kumano, Shunya Arai, Masataka Hosoi, Kazuki Taoka, Koki Ueda, Kumi Nakazaki, Yasuhiko Kamikubo, Mineo Kurokawa.
  • Organizer: International Society for Stem cell Research (ISSCR) annual meeting
  • Place of Presentation: Yokohama
• [Presentation] Generation of induced pluripotent stem cells from primary hematological malignancies (2011)
  • Author(s): Keiki Kumano, Shunya Arai, Masataka Hosoi, Kazuki Taoka, Koki Ueda, Kumi Nakazaki, Yasuhiko Kamikubo, Mineo Kurokawa
  • Organizer: 第73回日本血液学会学術集会
  • Place of Presentation: 名古屋
  • Year and Date: 2011-10-15
• [Presentation] Generation of induced pluripotent stem cells from primary hematological malignancies and search for the novel targeted therapy (2011)
  • Author(s): Keiki Kumano, Shunya Arai, Masataka Hosoi, Kazuki Taoka, Koki Ueda, Kumi Nakazaki, Yasuhiko Kamikubo, Mineo Kurokawa
  • Organizer: 第70回日本癌学会学術総会
  • Place of Presentation: 名古屋
  • Year and Date: 2011-10-04
• [Presentation] iPS細胞による白血病の病態解析 (2011)
  • Author(s): 熊野恵城、黒川峰夫
  • Organizer: 第15回日本がん分子標的治療学会
  • Place of Presentation: 東京
  • Year and Date: 2011-06-23
• [Presentation] Generation of induced pluripotent stem cells from primary hematological malignancies and search for the novel targeted therapy (2011)
  • Author(s): Keiki Kumano, Shunya Arai, Masataka Hosoi, Kazuki Taoka, Koki Ueda, Kumi Nakazaki, Yasuhiko Kamikubo, Mineo Kurokawa
  • Organizer: The 9^<th> Stem Cell Research Symposium
  • Place of Presentation: Tokyo
  • Year and Date: 2011-05-13
• [Presentation] Generation of induced pluripotent stem cells from primary hematological malignancies and search for the novel targeted therapy. (2011)
  • Author(s): Keiki Kumano, Shunya Arai, Masataka Hosoi, Kazuki Taoka, Koki Ueda, Kumi Nakazaki, Yasuhiko Kamikubo, and Mineo Kurokawa.
  • Organizer: The 9th Stem Cell Research Symposium
  • Place of Presentation: Tokyo