Analysis and basic research of targeted therapy for CML stem cells

2011 Fiscal Year Final Research Report

• Project/Area Number: 22790908
• Research Category: Grant-in-Aid for Young Scientists (B)
• Allocation Type: Single-year Grants
• Research Field: Hematology
• Research Institution: Nagoya University
• Principal Investigator: MINAMI Yosuke 名古屋大学, 医学系研究科, COE特任講師 (60513752)
• Project Period (FY): 2010 – 2011
• Keywords: 白血病 / 幹細胞 / キナーゼ阻害剤 / BCR-ABL / mTORシグナル

Research Abstract

Several mathematical models and ex-vivo examinations suggested that imatinib(IM) therapy does not eradicate BCR-ABL-positive leukemia stem cells(LSCs). In optimal responders to IM therapy, BCR-ABL transcripts in the HSC population tended to be more retentive than other populations. Treatment with the second-generation of ABL-tyrosine kinase inhibitors(2nd TKIs) induced more rapid reduction of BCR-ABL transcripts even in the HSC population. In Ph^+leukemia cells serially xenotransplanted into immunodeficient NOG mice, slow-cycling CD34^+cells were insensitive to IM. From comprehensive drug screening of other small compounds using this co-culturing system, we found that inhibitors of PI3K/AKT/mTOR-axis signaling, including rapamycin, were promising candidates. In vitro and in vivo, combination treatment with IM and rapamycin analogue, everolimus(RAD001), induced substantial cell death in the slow-cycling CD34^+population with p70-S6K dephosphorylation. The dual PI3K/mTOR inhibitor, NVP-BEZ235(BEZ), also induced substantial cell death including slow-cycling CD34^+cells at lower doses.

Research Products

• [Journal Article] Retention of CD34^+CML stem/progenitor cells during imatinib treatment and rapid decline after treatment with second-generation BCR-ABL inhibitors (2012)
  • Author(s): Y Minami, A Abe, M Minami, K Kitamura, J Hiraga, S Mizuno, K Ymamoto, M Sawa, Y Inagaki, K Miyamura, and T Naoe
  • Journal Title: Leukemia Volume: (in press)
  • Peer Reviewed
• [Journal Article] Treatment with mTOR inhibitor, everolimus(RAD001), overcomes resistance to imatinib in quiescent Ph-positive acute lymphoblastic leukemia cells (2011)
  • Author(s): Y Kuwatsuka, M Minami, Y Minami, K Sugimoto, F Hayakawa, Y Miyata, A Abe, DJ Goff, H Kiyoi and T Naoe
  • Journal Title: Blood Cancer Volume: 1 Pages: e17
  • Peer Reviewed
• [Journal Article] Expanded distribution of the T315I mutation among hematopoietic stem cells and progenitors in a chronic myeloid leukemia patient during imatinib-treatment (2010)
  • Author(s): Y Minami, T Kajiguchi, A Abe, T Ohno, H Kiyoi and T Naoe
  • Journal Title: Int J Hematol Volume: 92(40) Pages: 664-666
  • Peer Reviewed
• [Presentation] Retention of slow-cycling CD34^+cells during imatinib treatment and rapid decline after 2nd ABL-TKI treatment in Ph^+leukemia cells (2011)
  • Author(s): Y Minami, A Abe, M Minami, Y Kuwatsuka, N Fukushima, K Kitamura, J Hiraga, K Ymamoto, C Jamieson, and T Naoe
  • Organizer: 53rd ASH meeting
  • Place of Presentation: San Diego, USA
  • Year and Date: 20110000
• [Presentation] Treatment with the PI3K/mTOR inhibitor, NVP-BEZ235 overcomes resistance to imatinib in quiescent or T315I-mutated Ph-positive leukemia (2011)
  • Author(s): Y Minami, M Minami, N Fukushima, Y Kuwatsuka, and T Naoe
  • Organizer: 53rd ASH meeting
  • Place of Presentation: San Diego, USA
  • Year and Date: 20110000
• [Presentation] Treatment with mTOR inhibitors, everolimus and BEZ235 overcomesres istance to imatinib inBCR-ABL-positive leukemia quiescent cells (2011)
  • Author(s): 南陽介鍬塚八千代南美帆直江知樹
  • Organizer: 第9回日本臨床腫瘍学会総会(シンポジウム)
  • Place of Presentation: 横浜
  • Year and Date: 20110000