Blockade of PAI-1 eliminates leukemic stem cells

• Project/Area Number: 15H04301
• Research Category: Grant-in-Aid for Scientific Research (B)
• Allocation Type: Single-year Grants
• Section: 一般
• Research Field: Tumor biology
• Research Institution: Tokai University
• Principal Investigator: YAHATA Takashi 東海大学, 医学部, 准教授 (10398753)
• Co-Investigator(Renkei-kenkyūsha): ANDO Kiyoshi 東海大学, 医学部, 教授 (70176014) ; MIYATA Toshio 東北大学, 大学院・医学系研究科, 教授 (10222332) ; IBRAHIM Abd Aziz 東海大学, 医学部, 特定研究員(PD) (50738789)
• 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: ¥5,070,000 (Direct Cost: ¥3,900,000、Indirect Cost: ¥1,170,000); Fiscal Year 2016: ¥5,330,000 (Direct Cost: ¥4,100,000、Indirect Cost: ¥1,230,000); Fiscal Year 2015: ¥6,370,000 (Direct Cost: ¥4,900,000、Indirect Cost: ¥1,470,000)
• Keywords: 白血病 / 幹細胞 / ニッチ / 分子標的薬 / TGF-beta / 白血病幹細胞 / PAI-1 / TGF-b / がん幹細胞 / 薬剤耐性 / 繊維素溶解系 / 治療抵抗性 / 低分子化合物 / MT1-MMP

Outline of Final Research Achievements

We found that the expression of TGF-b-iPAI-1 signaling was selectively augmented in CML stem cells. CML cells expressing higher levels of iPAI-1 were resistance to imatinib treatment, indicating the iPAI-1 protects CML cells from TKI treatment. Combined treatment of imatinib plus PAI-1 inhibitor significantly decreased the persistent CML cells in the BM, reduced spleen size, and prolonged survival of CML-bearing mice. Importantly, blockade of PAI-1 activity in combination with TKI effectively eliminated CML stem cells in the BM, which resulted in losing their ability to initiate CML disease in the serial transplanted recipients. The effect of PAI-1 inhibitor to enhance the therapeutic effect of TKI was completely canceled by the administration of neutralizing antibody specific for MT1-MMP. Our findings provide evidence that blockade of PAI-1 activity could be a novel therapeutic approach for CML patients.

Research Products

• [Int'l Joint Research] NorthWestern University(米国)
• [Journal Article] Jagged 1-induced Notch activatio contributes to the acquisition of bortezomib resistance in myeloma cells (2017)
  • Author(s): Yukari Muguruma, Takashi Yahata, Takayuki Warita, Katsuyo Hozumi, Yoshihiko Nakamura, Rikio Suzuki, Mamoru Ito, Kiyoshi Ando
  • Journal Title: Blood Cancer Journal Volume: 7 Issue: 12 Pages: 1408-1408
  • DOI: 10.1038/s41408-017-0001-3
  • Peer Reviewed / Open Access
• [Journal Article] TGF-β-induced intracellular PAI-1 is responsible for retaining hematopoietic stem cells in the niche (2017)
  • Author(s): Yahata Takashi、Ibrahim Abd Aziz、Muguruma Yukari、Eren Mesut、Shaffer Alexander M.、Watanabe Nobuo、Kaneko Satoko、Nakabayashi Tetsuo、Dan Takashi、Hirayama Noriaki、Vaughan Douglas E.、Miyata Toshio、Ando Kiyoshi
  • Journal Title: Blood Volume: 130 Issue: 21 Pages: 2283-2294
  • DOI: 10.1182/blood-2017-02-767384
  • Peer Reviewed / Open Access / Int'l Joint Research
• [Journal Article] Comparison of the Gene Expression Profiles of Human Hematopoietic Stem Cells between Humans and a Humanized Xenograft Model (2017)
  • Author(s): Matsuzawa H, Matsushita H, Yahata T, Tanaka M, Ando K.
  • Journal Title: Tokai Journal of Experimental Clinical Medicine Volume: 42 Pages: 41-51
  • Peer Reviewed / Open Access
• [Journal Article] Maintenance of Bone Homeostasis by DLL1-Mediated Notch Signaling. (2017)
  • Author(s): Muguruma Y, Hozumi K, Warita H, Yahata T, Uno T, Ito M, Ando K.
  • Journal Title: J Cell Physiol. Volume: 印刷中 Issue: 9 Pages: 2569-2580
  • DOI: 10.1002/jcp.25647
  • Peer Reviewed / Open Access / Int'l Joint Research / Acknowledgement Compliant
• [Journal Article] Comparison of the Gene Expression Profiles of Human Hematopoietic Stem Cells between Humans and a Humanized Xenograft Model. (2017)
  • Author(s): Matsuzawa H, Matsushita H, Yahata T, Tanaka M, Ando K.
  • Journal Title: Tokai J Exp Clin Med. Volume: 42 Pages: 41-51
  • Peer Reviewed
• [Journal Article] Common marmoset CD117-positive hematopoietic cells possess multipotency (2015)
  • Author(s): Shimada S, Nunomura S, Mori S, Suemizu H, Itoh T, Takabayashi S, Okada Y, Yahata T, Shiina T, Katoh H, Suzuki R, Tani K, Ando K, Yagita H, Habu S, Sasaki E, Kametani Y.
  • Journal Title: Int Immune Volume: 27 Issue: 11 Pages: 567-577
  • DOI: 10.1093/intimm/dxv031
  • Peer Reviewed / Open Access / Int'l Joint Research
• [Presentation] G-CSF-induced cAMP-PKA-CREB pathway counteracts TGF-β-PAI-1 signaling-dependent retention of HSCs in the niche (2017)
  • Author(s): Takashi Yahata
  • Organizer: 59th American Society of Hematology Annual Meeting and Exposition
  • Int'l Joint Research
• [Presentation] G-CSF-induced cAMP-PKA-CREB pathway counteracts TGF-β-PAI-1 signaling-dependent retention of HSCs (2017)
  • Author(s): Abd Aziz Ibrahim, Takashi Yahata
  • Organizer: 第７９回日本血液学会学術集会
• [Presentation] TGF-b induced intracellular PAI-1 is a critical regulator HSC localization in the niche (2016)
  • Author(s): アブドゥル アジズ、八幡 崇
  • Organizer: 第７８回日本血液学会学術集会
  • Place of Presentation: パシフィコ横浜（神奈川県横浜市）
  • Year and Date: 2016-10-13
• [Presentation] Jagged-1-Notch interaction in the niche is responsible for acquisition of drug-resistance (2016)
  • Author(s): 六車ゆかり、八幡 崇
  • Organizer: 第７８回日本血液学会学術集会
  • Place of Presentation: パシフィコ横浜（神奈川県横浜市）
  • Year and Date: 2016-10-13
• [Presentation] Intracellular PAI-1 is a critical regulator of hematopoietic stem and progenitor cell localization in the niche (2016)
  • Author(s): Yahata T, Ibrahim AA, Muguruma Y, Kaneko S, Miata T, Ando K
  • Organizer: Gordon Research Conference
  • Place of Presentation: Ventura, CA
  • Year and Date: 2016-02-14
  • Int'l Joint Research