Targeting malignant stem cells in BCR-ABL positive leukemia

• Project/Area Number: 25461424
• 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: Iwasaki Hiromi 九州大学, 大学病院, 准教授 (20403925)
• Project Period (FY): 2013-04-01 – 2016-03-31
• Project Status: Completed (Fiscal Year 2015)
• Budget Amount: ¥4,940,000 (Direct Cost: ¥3,800,000、Indirect Cost: ¥1,140,000); Fiscal Year 2015: ¥1,560,000 (Direct Cost: ¥1,200,000、Indirect Cost: ¥360,000); Fiscal Year 2014: ¥1,690,000 (Direct Cost: ¥1,300,000、Indirect Cost: ¥390,000); Fiscal Year 2013: ¥1,690,000 (Direct Cost: ¥1,300,000、Indirect Cost: ¥390,000)
• Keywords: 慢性骨髄性白血病 / 白血病幹細胞

Outline of Final Research Achievements

In the present study, we got several important findings about the property of CML stem/progenitor cells. First, the frequencies of BCR-ABL positive clone in CD34+CD38- stem cell fraction varied from only 1% to 100% at diagnosis, suggesting that CML stem cells do not necessarily outgrow normal stem cells. On the other hand, the common myeloid progenitor (CMP) fraction markedly expanded in all cases, and the majority of these cells were positive for BCR-ABL FISH, indicating that the growth advantage of CML clone is obtained at the CMP stage. Importantly, leukemic CMPs suppressed the expression of IRF8, a transcription factor in the granulocyte lineage, which might play some role in the cell proliferation. The frequencies of BCR-ABL positive clone in the stem cell fraction strongly correlated with Sokal scores and, more interestingly, with the numbers of megakaryocyte progenitors, suggesting that “megakaryocyte niche” play some role in the survival and self-renewal of CML stem cells.

Research Products

• [Journal Article] α-Mannan induces Th17-mediated pulmonary graft-versus-host disease in mice. (2015)
  • Author(s): Uryu H, Hashimoto D, Kato K, Hayase E, Matsuoka S, Ogasawara R, Takahashi S, Maeda Y, Iwasaki H, Miyamoto T, Saijo S, Iwakura Y, Hill GR, Akashi K, Teshima T.:
  • Journal Title: Blood Volume: 125 Issue: 19 Pages: 3014-23
  • DOI: 10.1182/blood-2014-12-615781
  • Peer Reviewed / Open Access
• [Journal Article] Preserved in vivo reconstitution ability of PBSCs cryopreserved for a decade at -80 °C. (2015)
  • Author(s): Shima T, Iwasaki H, Yamauchi T, Kadowaki M, Kiyosuke M, Mochimaru T, Takenaka K, Miyamoto T, Akashi K, Teshima T.
  • Journal Title: Bone Marrow Transplant Volume: 50 Issue: 9 Pages: 1195-1200
  • DOI: 10.1038/bmt.2015.147
  • Peer Reviewed
• [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] 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] 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
• [Journal Article] The BALB/c-specific polymorphic SIRPA enhances its affinity for human CD47, inhibiting phagocytosis against human cells to promote xenogeneic engraftment. (2014)
  • Author(s): Iwamoto C
  • Journal Title: Exp Hematol Volume: 42 Issue: 3 Pages: 163-171
  • DOI: 10.1016/j.exphem.2013.11.005
  • Peer Reviewed
• [Presentation] Pomalidomide+Low-Dose Dexamethasone in Japanese Patients with Relapsed/Refractory Multiple Myeloma.岩﨑浩己、他 (2015)
  • Author(s): 岩﨑浩己、他
  • Organizer: 第77回日本血液学会総会
  • Place of Presentation: 金沢
  • Year and Date: 2015-10-17
• [Presentation] Identification of the Human Unipotent Megakaryocyte Progenitor, and Its Pathophysiological Roles in Human Thrombopoietic Disorders. (2014)
  • Author(s): Kohta Miyawaki, Hiromi Iwasaki, Koichi Akashi.
  • Organizer: 第56回米国血液学会
  • Place of Presentation: San Francisco
  • Year and Date: 2014-12-06 – 2014-12-09
• [Presentation] MM-004: A Phase 1, Dose-Escalation Study to Determine the Maximum Tolerated Dose, Safety, Efficacy, and Pharmacokinetics of Pomalidomide Alone or in Combination with Dexamethasone in Patients with Refractory or Relapsed and Refractory Multiple Myeloma in Japan. (2014)
  • Author(s): Shinsuke Iida, Hiromi Iwasaki, Takaaki Chou, Kensei Tobinai, Kazutaka Sunami, Yoshiaki Ogawa, Mari Kurihara, Shuichi Midorikawa, Mohamed H. Zaki, Thomas Derr, Kosei Matsue.
  • Organizer: 第56回米国血液学会
  • Place of Presentation: San Francisco
  • Year and Date: 2014-12-06 – 2014-12-09
• [Presentation] Human megakaryocyte progenitor emerges independent of megakaryocyte⁄erythrocyte progenitor. (2014)
  • Author(s): Kohta Miyawaki, Hirotake Kusumoto, Hiromi Iwasaki, Koichi Akashi.
  • Organizer: 第76回日本血液学会
  • Place of Presentation: 大阪
  • Year and Date: 2014-10-31 – 2014-11-02
• [Presentation] The clinical impact of novel alternative splicing of BCR-ABL in chronic myeloid leukemia. (2014)
  • Author(s): Junichiro Yuda, Toshihiro Miyamoto, Jun Odawara, Yoshikane Kikushige, Takahiro Shima, Taro Tochigi, Masayasu Hayashi, Yuichiro Senba, Goichi Yoshimoto, Kenjiro Kamezaki, Koji Kato, Tadafumi Iino, Katsuto Takenaka, Hiromi Iwasaki, Shinichi Mizuno, Yasuyuki Ohkawa, Koichi Akashi.
  • Organizer: 第76回日本血液学会
  • Place of Presentation: 大阪
  • Year and Date: 2014-10-31 – 2014-11-02
• [Presentation] Update of a phase 1⁄2 study of ponatinib in Japanese patients with Philadelphia positive leukemias. (2014)
  • Author(s): Arinobu Tojo, Taiichi Kyo, Kazuhito Yamamoto, Naoto Takahashi, Hirohisa Nakamae, Yukio Kobayashi, Tetsuzo Tauchi, Shinichiro Okamoto, Koichi Miyamura, Hiromi Iwasaki, Kiyohiko Hatake, Itaru Matsumura, Noriko Usui, Kumiko Yanase, Simin Hu, Chtistopher Turner, Tomoki Naoe, Kazuma Ohyashiki.
  • Organizer: 第76回日本血液学会
  • Place of Presentation: 大阪
  • Year and Date: 2014-10-31 – 2014-11-02
• [Presentation] INITIAL OCCUPANCY OF LEUKEMIC STEM CELL CORRELATES WITH PROGNOSTIC FACTOR IN CHRONIC MYELOID LEUKEMIA PATIENTS (2013)
  • Author(s): Hiromi Iwasaki
  • Organizer: 第18回ヨーロッパ血液学会
  • Place of Presentation: ストックホルム、スウェーデン
• [Book] Molecular Pathogenesis and Treatment of Chronic Myelogenous Leukemia. Chapter 1 Identification and Biology of CML Stem Cells. (2016)
  • Author(s): Hiromi Iwasaki and Koichi Akashi
  • Total Pages: 193
  • Publisher: Springer Japan
• [Remarks] 九州大学医学部第一内科（病態修復内科）
  • URL: http://www.1nai.med.kyushu-u.ac.jp
• [Remarks] http://www.1nai.med.kyushu-u.ac.jp