Molecular mechanisms and therapeutic approach of residual leukemia

• Project/Area Number: 19390261
• Research Category: Grant-in-Aid for Scientific Research (B)
• Allocation Type: Single-year Grants
• Section: 一般
• Research Field: Hematology
• Research Institution: Nagoya University
• Principal Investigator: NAOE Tomoki Nagoya University, 大学院・医学系研究科, 教授 (50217634)
• Co-Investigator(Kenkyū-buntansha): KATSUMI Akira 名古屋大学, 大学院・医学系研究科, 特任講師 (80378025)
• Project Period (FY): 2007 – 2009
• Project Status: Completed (Fiscal Year 2009)
• Budget Amount: ¥18,720,000 (Direct Cost: ¥14,400,000、Indirect Cost: ¥4,320,000); Fiscal Year 2009: ¥4,420,000 (Direct Cost: ¥3,400,000、Indirect Cost: ¥1,020,000); Fiscal Year 2008: ¥4,420,000 (Direct Cost: ¥3,400,000、Indirect Cost: ¥1,020,000); Fiscal Year 2007: ¥9,880,000 (Direct Cost: ¥7,600,000、Indirect Cost: ¥2,280,000)
• Keywords: 白血病 / 幹細胞 / 化学療法 / 耐性 / 造血ニッチ / 接着 / ホーミング / ニッシェ

Research Abstract

To identify the leukemia-propagating stem cell fraction of Philadelphia chro-mosome-positive (Ph+) leukemia, we serially transplanted human leukemia cells from patients with chronic myeloid leukemia blast crisis or Ph+ acute lymphoblastic leukemia into NOD/SCID/IL-2Rcγ^<null> mice. Engrafted cells were almost identical to the original leukemia cells. CD34+CD38-CD19+, CD34+38+CD19+, and CD34-CD38+CD19+ fractions could self-renew and transfer the leukemia, whereas the CD34-CD38+CD19+ fraction did not stably propagate in NOD/SCID mice. These findings suggest that leukemia-repopulating cells in transformed Ph+ leukemia are included in a lineage-committed but multilayered fraction, and that CD34+ leukemia cells potentially emerge from CD34- populations.

Research Products

• [Journal Article] BCR-ABL-independent and RAS / MAPK pathway-dependent form of imatinib resistance in Ph-positive acute lymphoblastic leukemia cell line with activation of EphB4 (2010)
  • Author(s): Suzuki M, Abe A, Imagama S, Nomura Y, Tanizaki R, Minami Y, Hayakawa F, Ito Y, Katsumi A, Yamamoto K, Emi N, Kiyoi H, Naoe T
  • Journal Title: Eur J Haematol 84 Pages: 229-38
  • Peer Reviewed
• [Journal Article] BCR-ABL-independent and RAS/MAPK pathway-dependent form of imatinib resistance in Ph-positive acute lymphoblastic leukemia cell line with activation of EphB4 (2010)
  • Author(s): Suzuki M, et al.
  • Journal Title: Eur J Haematol 84 Pages: 229-238
  • Peer Reviewed
• [Journal Article] rrespective of CD34 expression, lineage-committed cell fraction reconstitutes and re-establishes transformed Philadelphia chromosome-positive leukemia in NOD/SCID/IL-2R gammac mice (2009)
  • Author(s): Tanizaki R, Nomura Y, Miyata Y, Minami Y, Abe A, Hanamura A, Sawa M, Murata M, Kiyoi H, Matsushita T, Naoe T
  • Journal Title: Cancer Sci (Epub ahead of print)
  • Peer Reviewed
• [Journal Article] KW-2449, a novel multikinase inhibitor, suppresses the growth of leukemia cells with FLT3 mutations or T315I-mutated BCR/ABL translocation (2009)
  • Author(s): Shiotsu Y, Kiyoi H, Ishikawa Y, Tanizaki R, Shimizu M, Umehara H, Ishii K, Mori Y, Ozeki K, Minami Y, Abe A, Maeda H, Akiyama T, Kanda Y, Sato Y, Akinaga S, Naoe T
  • Journal Title: Blood 114 Pages: 1607-17
  • Peer Reviewed
• [Journal Article] Circumventing resistance to imatinib therapy in chronic myeloid leukemia (2009)
  • Author(s): Minami Y, Naoe T
  • Journal Title: Gan To Kagaku Ryoho 36(4) Pages: 544-7
  • Peer Reviewed
• [Journal Article] Irrespective of CD34 expression, lineage-committed cell fraction reconstitutes and re-establishes transformed Philadelphia chromosome-positive leukemia in NOD/SCID/IL-2Rgammac mice (2009)
  • Author(s): Tanizaki R, et. al.
  • Journal Title: Cancer Sci (in Press)
  • Peer Reviewed
• [Journal Article] KW-2449, a novel multikinase inhibitor, suppresses the growth of leukemia cells with FLT3 mutations or T315I-mutated BCR/ABL translocation (2009)
  • Author(s): Shiotsu Y, et al.
  • Journal Title: Blood 114 Pages: 1607-1617
  • Peer Reviewed
• [Journal Article] GATA-1 and GATA-2 binding to 3'enhancer of WT1 gene is essential for its transcription in acute leukemia and solid tumor cell lines. (2009)
  • Author(s): Furuhata A, Naoe T, et al
  • Journal Title: Leukemia. 12(in press)
  • Peer Reviewed
• [Journal Article] Retention but significant reduction of BCR-ABL transcript in hematopoietic stem cells in chronic myelogenous leukemia after imatinib therapy (2008)
  • Author(s): Abe A, Minami Y, Hayakawa F, Kitamura K, Nomura Y, Murata M, Katsumi A, Kiyoi H, Jamieson CH, Wang JY, Naoe T
  • Journal Title: Int J Hematol 88 Pages: 471-5
  • NAID: 10023971017
  • Peer Reviewed
• [Journal Article] BCR-ABL-transformed GMP as myeloid leukemic stem cells (2008)
  • Author(s): Minami Y, Stuart SA, Ikawa T, Jiang Y, Banno A, Hunton IC, Young DJ, Naoe T, Murre C, Jamieson CH, Wang JY
  • Journal Title: Proc Natl Acad Sci U S A 105 Pages: 17967-72
  • Peer Reviewed
• [Journal Article] Mutational analysis of SOS1 gene in acute myeloid leukemia (2008)
  • Author(s): Tanizaki R, Katsumi A, Kiyoi H, Kunishima S, Iwasaki T, Ishikawa Y, Kobayashi M, Abe A, Matsushita T, Watanabe T, Kojima T, Kaibuchi K, Kojima S, Naoe T
  • Journal Title: Int J Hematol 88 Pages: 460-2
  • NAID: 10023970986
  • Peer Reviewed
• [Journal Article] Prognostic implication and biological roles of RhoH in acute myeloid leukaemia (2008)
  • Author(s): Iwasaki T, Katsumi A, Kiyoi H, Tanizaki R, Ishikawa Y, Ozeki K, Kobayashi M, Abe A, Matsushita T, Watanabe T, Amano M, Kojima T, Kaibuchi K, Naoe T
  • Journal Title: Eur J Haematol 81 Pages: 454-60
  • Peer Reviewed
• [Journal Article] Abnormal cytoplasmic dyslocalisation and/or reduction of nucle ophosmin protein level rarely occurs in myelodysplastic syndromes. (2008)
  • Author(s): Ishikawa Y, Naoe T, et al
  • Journal Title: Leuk Lymphoma. 49 Pages: 2359-64
  • Peer Reviewed
• [Journal Article] Retention but significant reduction of BCR-ABL transcript in hematopoietic stem cells in chronic myelogenous leukemia after imatinib therapy. (2008)
  • Author(s): Abe A, Naoe T, et al
  • Journal Title: Int J Hematol. 88 Pages: 471-5
  • NAID: 10023971017
  • Peer Reviewed
• [Journal Article] Clinical significance of nuclear non-phosphorylated beta-catenin in acute myeloid leukaemia and myelodysplastic syndrome (2008)
  • Author(s): Jinglan Xu
  • Journal Title: Br J Haematol. 140 Pages: 394-401
  • Peer Reviewed
• [Journal Article] LRP16 is fused to RUNX1 in monocytic leukemia cell line with t(11;21)(q13;q22) (2007)
  • Author(s): Imagama S, Abe A, Suzuki M, Hayakawa F, Katsumi A, Emi N, Kiyoi H, Naoe T
  • Journal Title: Eur J Haematol 79 Pages: 25-31
  • Peer Reviewed
• [Journal Article] Homing, proliferation and survival sites of human leukemia cells in vivo in immunodeficient mice (2007)
  • Author(s): Ninomiya M, Abe A, Katsumi A, Xu J, Ito M, Arai F, Suda T, Ito M, Kiyoi H, Kinoshita T, Naoe T
  • Journal Title: Leukemia 21 Pages: 136-42
  • Peer Reviewed
• [Journal Article] Homing, proliferation and survival sites of human leukemia cells in vivo in immunodeficient mice (2007)
  • Author(s): Manabu Ninomiya
  • Journal Title: Leukemia 21 Pages: 136-42
  • Peer Reviewed
• [Journal Article] Lyn is an important component of the signal transduction pathway specific to FLT3/ITD and can be a therapeutic target in the treatment of AML with FLT3/ITD (2007)
  • Author(s): Mitsunori Okamoto
  • Journal Title: Leukemia 18
  • Peer Reviewed
• [Presentation] Treatment with mTOR Inhibitor, Everolimus (RAD001) Overcomes Resistance to Imatinib in Ph-Leukemia Quiescent or T315I-Mutated Cells (2009)
  • Author(s): Minami Y, et al.
  • Organizer: The 51th American Society of Hematology
  • Place of Presentation: New Orleans, LA
  • Year and Date: 2009-12-07
• [Presentation] Treatment with mTOR Inhibitor, Everolimus (RAD001) Overcomes Resistance to Imatinib in Ph-Leukemia Quiescent or T315I-Mutated Cells (2009)
  • Author(s): Minami Y, Minami M, Kuwatsuka Y, Tanizaki R, Nomura Y, Abe A, Kiyoi H, Naoe T
  • Organizer: The 51st ASH Annual Meeting and Exposition
  • Place of Presentation: New Orleans
• [Presentation] Treatment with Bortezomib Overcomes Resistance to Imatinib in Ph-Leukemia Quiescent Cells (2009)
  • Author(s): Kuwatsuka Y, Minami Y, Tanizaki R, Minami M, Abe A, Nomura Y, Kiyoi H, Naoe T
  • Organizer: The 51st ASH Annual Meeting and Exposition
  • Place of Presentation: New Orleans, LA
• [Presentation] FLT3/ITD Regulates Leukemia Cell Adhesion throughα4β1 Integrin and Pyk2 Signaling (2009)
  • Author(s): Katsumi A, Kiyoi H, Abe A, Naoe T
  • Organizer: The 51st ASH Annual Meeting and Exposition
  • Place of Presentation: New Orleans, LA
• [Presentation] Evaluation of BCR-ABL-positive leukemia stem cells: strategies for overcoming the resistance to imatinib (2009)
  • Author(s): Y Minami
  • Organizer: Gordon Research Conferences, Stem Cells, Cancer (Selected plenary speech, poster presentation), LesDiablerets
  • Place of Presentation: Switzerland
• [Presentation] Evaluation of BCR-ABL-positive leukemia stem cells with imatinib-therapy and apoptosis induced by bortezomib-treatment (2009)
  • Author(s): 南陽介, 安部明弘, 鍬塚八千代, 野村由佳, 谷崎亮平, 直江知樹
  • Organizer: 第7回幹細胞シンポジウム(一般演題)
  • Place of Presentation: 東京
• [Presentation] Ph陽性白血病幹細胞におけるイマチニブ耐性とボルテゾミブによる克服の可能性 (2009)
  • Author(s): 南陽介, 鍬塚八千代, 谷崎亮平, 野村由佳, 安部明弘, 清井仁, 直江知樹
  • Organizer: 第18回日本アポトーシス研究会(一般口演)
  • Place of Presentation: 長崎
• [Presentation] Ph陽性白血病幹細胞におけるイマチニブ耐性とボルテゾミブによる克服の可能性 (2009)
  • Author(s): 南陽介鍬塚八千代谷崎亮平安部明弘直江知樹
  • Organizer: 第68回日本癌学会総会
  • Place of Presentation: 横浜(一般口演)
• [Presentation] Transformation of E2A-deficient pluripotent progenitors by BCR-ABL generates imatinib-resistant leukemic stem cells (2008)
  • Author(s): Minami Y, Abe A, Ikawa T, Stuart S, Jamieson CHM, Naoe T
  • Organizer: Wang JYJ 50th ASH meeting
  • Place of Presentation: San Francisco, USA
• [Presentation] Hsp90 inhibitor, 17-AAG overcome resistance of FLT3-inhibitor in MOLM13N676K (2008)
  • Author(s): Y Minami, Y Nomura, A Abe, R Tanizaki, Y Shiotsu, S Akinaga, H Kiyoi, T Naoe
  • Organizer: 50th ASH meeting
  • Place of Presentation: San Francisco, USA
• [Presentation] 慢性骨髄性白血病幹前駆細胞に対するイマチニブの効果:マウス多能性造血細胞モデル及び治療後残存腫瘍解析 (2008)
  • Author(s): 南陽介、安部明弘、伊川友活、Scott Stuart, 早川文彦、北村邦朗、野村由佳、Catriona Jamieson, Jean Wang, 直江知樹
  • Organizer: 第70回日本血液学会総会
  • Place of Presentation: 京都国際会議場
• [Presentation] Philadelphia染色体陽性急性リンパ芽球性白血病由来Imatinib耐性株の樹立とその耐性化機序の解析 (2008)
  • Author(s): 西岡百子、安部明弘、今釜静香、谷崎亮平、勝見章、南陽介、早川文彦、山本一仁、直江知樹
  • Organizer: 第70回日本血液学会総会
  • Place of Presentation: 京都国際会議場
• [Presentation] FLT3/ITD regulates leukemia cell adhesion through a4b1 integrin and Pyk2 signaling (2008)
  • Author(s): 勝見章、清井仁、安部明弘、谷崎亮平、松下正、小嶋哲人、直江知樹
  • Organizer: 第71回日本血液学会学術総会
  • Place of Presentation: 京都国際会議場
• [Presentation] Evaluation of residual leukemia stem cells in chronic myeloid leukemia with imatinib therapy (2008)
  • Author(s): 南陽介, 安部明弘, 鍬塚八千代, 早川文彦, 谷崎亮平, 勝見章, 清井仁, 直江知樹
  • Organizer: 第67回日本癌学会総会(ワークショップ)
  • Place of Presentation: 名古屋