Tyrosine kinase inhibitor induce CML migration to stromal microenvironment through Lyn/CXCR4 interactions in lipid rafts

2011 Fiscal Year Final Research Report

• Project/Area Number: 21591223
• Research Category: Grant-in-Aid for Scientific Research (C)
• Allocation Type: Single-year Grants
• Section: 一般
• Research Field: Hematology
• Research Institution: Juntendo University
• Principal Investigator: TABE Yoko 順天堂大学, 医学部, 准教授 (70306968)
• Co-Investigator(Kenkyū-buntansha): JIN Linhua 順天堂大学, 医学部, ポスドクフェロー (90531955) ; IWABUCHI Kazuhisa 順天堂大学, 医療看護学部, 教授 (10184897) ; TOMIKAWA Naoki (ICHIKAWA Naoki) 福島県立医科大学, 医学部, 助教 (80468587)
• Project Period (FY): 2009 – 2011
• Keywords: 慢性骨髄性白血病 / イマチニブ / CXCR4 / Lyn

Research Abstract

p210Bcr-Abl tyrosine kinase inhibits CXCR4-mediated migration of chronic myeloid leukemia(CML) cells to bone marrow stroma. In turn, exposure of CML cells to a tyrosine kinase inhibitor(TKI) enhances migration of CML cells toward stromal cell layers and promotes nonpharmacological resistance to imatinib. Src-related kinase Lyn is known to interact with CXCL12/CXCR4 signaling and is directly activated by p210Bcr-Abl. TKI treatment under co-culture with mesenchymal stromal cells induced CXCR4 localization in the lipid raft fraction, which further co-localized with active phosphorylated form of Lyn(LynTyr396) in CML cells. Lyn inhibition or cholesterol depletion abrogated imatinib-induced migration. These findings demonstrate the critical role of lipid rafts in imatinib-induced CML migration and lodging within the bone marrow microenvironment through the compartmental changes of the multivalent CXCR4 and Lyn complex.

Research Products

• [Journal Article] Role of stromal microenvironment in nonpharmacological resistance of CML to imatinib through Lyn/CXCR4 interactions in lipid rafts (2012)
  • Author(s): Tabe Y, Jin L, Iwabuchi K, Wang R, Ichikawa N, Miida T, Cortes J, Andreeff M, Konopleva M.
  • Journal Title: Leukemia Volume: 26 Pages: 883-92
  • Peer Reviewed
• [Journal Article] Effects of PPAR γ Ligands on Leukemia (2012)
  • Author(s): Tabe Y, Konopleva M. Andreeff M, Ohsaka A.
  • Journal Title: PPAR research Volume: (in press)
  • Peer Reviewed
• [Journal Article] Antiproliferative and proapoptotic activity of GUT-70 mediated through potent inhibition of Hsp90 in mantle cell lymphoma (2011)
  • Author(s): Jin L, Tabe Y, Kimura S, Zhou Y, Kuroda J, Asou H, Inaba T, Konopleva M, Andreeff M, Miida T.
  • Journal Title: Br J Cancer Volume: 104 Pages: 91-100
  • Peer Reviewed
• [Journal Article] MDM2 antagonist Nutlin-3 enhances bortezomib-mediated mitochondrial apoptosis in TP53-mutated mantle cell lymphoma (2010)
  • Author(s): Jin L, Tabe Y, Kojima K, Zhou Y, Pittaluga S, Konopleva M, Miida T, Raffeld M.
  • Journal Title: Cancer Lett Volume: 229 Pages: 161-170
  • Peer Reviewed
• [Journal Article] Selective FLT3 inhibitor FI-700 neutralizes Mcl-1 and enhances p53-mediated apoptosis in AML cells with activating mutations of FLT3 via Mcl-1/Noxa axis (2010)
  • Author(s): Kojima K, Konopleva M, Tsao T, Andreeff M, Ishida H, Shiotsu Y, Jin L, Tabe Y, NakakumaH.
  • Journal Title: Leukemia Volume: 24 Pages: 33-43
  • Peer Reviewed
• [Journal Article] The MDM2 antagonist Nutlin-3 displays anti-proliferative and pro-apoptotic activity in mantle cell lymphoma (2009)
  • Author(s): Tabe Y, Sebasigari D, Jin L, Rudelius M, Davies-Hill T, Miyake K, Miida T, Pittaluga S, Raffeld M.
  • Journal Title: Clin. Cancer Res Volume: 15 Pages: 933-942
  • Peer Reviewed
• [Journal Article] Therapeutic targeting of microenvironmental interactions in leukemia : Mechanisms and approaches (2009)
  • Author(s): Konopleva M, Tabe Y, Zeng Z, Andreeff M.
  • Journal Title: Drug Resist Updat Volume: 13 Pages: 103-113
  • Peer Reviewed
• [Journal Article] 白血病診断と分子標的療法に関する検討 (2009)
  • Author(s): 田部陽子
  • Journal Title: 臨床病理 Volume: Vol.57 No.2 Pages: 137-145
  • Peer Reviewed
• [Presentation] Bone marrow-derived adipocytes promote differentiation, proliferation and survival of acute monoblastic leukemia cells (2011)
  • Author(s): Tabe Y, Jin L, Konopleva M, Andreeff M, Ohsaka A, Miida T.
  • Organizer: American Society of Hematology Annual Meeting
  • Place of Presentation: San Diego, USA
  • Year and Date: 20111200
• [Presentation] The anti-proliferative effects of tricyclic coumarin GUT-70 as an Hsp90 inhibitor in mantle cell lymphoma (2011)
  • Author(s): Jin L, Kimura S, Zhou Y, Kuroda J, Asou H, Inaba T, Miida T, Konopleva M, Andreeff M, Tabe Y.
  • Organizer: American Society of Hematology Annual Meeting
  • Place of Presentation: San Diego, USA
  • Year and Date: 20111200
• [Presentation] TGF-βneutralizing antibody 1D11 inhibits LIF-JAK-Stat3 signaling and enhances cytarabine induced apoptosis in AML cells in bone marrow microenvironment (2011)
  • Author(s): Tabe Y, Shi Y, Zeng Z, Jin L, Zhou Y, Miida T, Andreeff M, Konopleva M.
  • Organizer: American Society of Hematology Annual Meeting
  • Place of Presentation: San Diego, USA
  • Year and Date: 20111200
• [Presentation] Growth-inhibitory effects of a Class IA PI3K inhibitor GDC-0941 are modulated by hypoxia-induced mTOR pathway activation in mantle cell lymphoma (2011)
  • Author(s): Tabe Y, Jin L, Miida T, Andreeff M, Konopleva M.
  • Organizer: American Society of Hematology Annual Meeting
  • Place of Presentation: San Diego, USA
  • Year and Date: 20111200
• [Presentation] 低酸素骨髄微小環境下での残存白血病に対するPI3KとFLT3.阻害の抗腫瘍作用機序 (2011)
  • Author(s): 田部陽子、金林花、三井田孝
  • Organizer: 日本臨床検査医学会学術集会
  • Place of Presentation: 岡山
  • Year and Date: 20111100
• [Presentation] 白血病細胞の増殖、分化、細胞死および骨髄微小循環 (2011)
  • Author(s): 田部陽子
  • Organizer: 前臨床血液研究会
  • Place of Presentation: 東京
  • Year and Date: 20111100
• [Presentation] 白血病細胞の増殖、分化、細胞死および骨髄微小環境 (2011)
  • Author(s): 田部陽子
  • Organizer: 日本検査血液学会学術集会
  • Place of Presentation: 岡山
  • Year and Date: 20110700
• [Presentation] マントル細胞リンパ腫の分子標的 (2011)
  • Author(s): 田部陽子
  • Organizer: 東海大学悪性リンパ腫研究会
  • Place of Presentation: 神奈川
  • Year and Date: 20110700
• [Presentation] The Anti-Proliferative Effects of Tricyclic Coumarin GUT-70 as An Hsp90 Inhibitor In Mantle Cell Lymphoma (2010)
  • Author(s): Jin L, Kimura S, Zhou Y, Kuroda J, Asou H, Inaba T, Andreeff M, Miida T, Tabe Y.
  • Organizer: American Society of Hematology Annual Meeting
  • Place of Presentation: Orlando, USA
  • Year and Date: 20101200
• [Presentation] MDM2 antagonist nutlin-3 enhances bortezomib-mediated mitochondrial apoptosis in TP53-mutated mantle cell lymphoma (2010)
  • Author(s): Tabe Y, Jin L, Kojima K, Zhou Y, Pittaluga S, Konopleva M, Miida T, Raffeld M.
  • Organizer: American Society of Hematology Annual Meeting
  • Place of Presentation: Orlando, USA
  • Year and Date: 20101200
• [Presentation] Efficacy and Mechanisms of Apoptosis Induction by Simultaneous Inhibition of PI3K with GDC-0941 and Blockade of Bcl-2(ABT-737) or FLT3(Sorafenib) In AML Cells In the Hypoxic Bone Marrow Microenvironment (2010)
  • Author(s): Jin L, Tabe Y, Miida T, Andreeff M, Konopleva M.
  • Organizer: American Society of Hematology Annual Meeting
  • Place of Presentation: Orlando, USA
  • Year and Date: 20101200
• [Presentation] Inhibition of TGF-βand CXCR4 signaling promotes cell cycle arrest and apoptosis in leukemic cells co-cultured with stromal cells (2010)
  • Author(s): Zhou Y, Tabe Y, Jin L, Miida T, Zeng Z, Andreeff M, Konopleva M.
  • Organizer: American Society of Hematology Annual Meeting
  • Place of Presentation: Orlando, USA
  • Year and Date: 20101200
• [Presentation] The Tricyclic Coumarin GUT-70 Induces Apoptosis and Cell Cycle Arrest Preferentially in Mantle Cell Lymphomas with Mutant p53 New Orleans (2009)
  • Author(s): Jin L, Kimura S, Zhou Y, Kuroda J, Asou H, Inaba T, Andreeff M, Miida T, Tabe Y.
  • Organizer: Annual Meeting of American Society of Hematology(ASH)
  • Place of Presentation: San Francisco, U. S. A
  • Year and Date: 20091205-08
• [Presentation] PTEN Regulates SYK-Directed AKT Activation in MCL New Orleans (2009)
  • Author(s): Rudelius M, Pittaluga S, Sebasigari D, Davies-Hill T, Klier M, Quintanilla-Martinez L, Fend F, Tabe Y, Raffeld M.
  • Organizer: Annual Meeting of American Society of Hematology(ASH)
  • Place of Presentation: San Francisco, U. S. A
  • Year and Date: 20091205-08
• [Presentation] Selective FLT3 Inhibitor FI-700 Neutralizes Mcl-1 and Enhances p53-Mediated Apoptosis in Acute Myeloid Leukemia(AML) Cells with Activating Mutations of FLT3 Via Mcl-1/Noxa Axis New Orleans (2009)
  • Author(s): Kojima K, Konopleva M, Tsao T, Andreeff M, Ishida H, Shiotsu Y, Jin L, Tabe Y, Nakakuma H.
  • Organizer: Annual Meeting of American Society of Hematology(ASH)
  • Place of Presentation: San Francisco, U. S. A
  • Year and Date: 20091205-08
• [Presentation] チロシンキナーゼ阻害剤による慢性骨髄性白血病のCXCR4シグナル活性化と骨髄定着 (2009)
  • Author(s): 金林花、周奕欣、田部陽子、三井田孝
  • Organizer: 第72回日本血液学会学術集会
  • Place of Presentation: 横浜
  • Year and Date: 20090900
• [Presentation] マントル細胞リンパ腫に対するプロテアソーム阻害剤BortezomibとMDM2阻害剤Nutlin-3の抗腫瘍相乗効果 (2009)
  • Author(s): 田部陽子, 金林花, 周奕欣, 三井田孝
  • Organizer: 第56回日本臨床検査医学会学術集会
  • Place of Presentation: 札幌市
  • Year and Date: 20090826-29
• [Book] 白血球分類のナビゲータ (2011)
  • Author(s): 田部陽子、佐藤尚武、田中千晶
  • Total Pages: 61
  • Publisher: シスメックス株式会社
• [Remarks]
  • URL: http://www.juntendo.ac.jp/graduate/laboratory/labo/byotaikaiseki/index.html