Integrative genomic and proteomic analyses of low-dose ionizing radiation in EBV infected-B cells

• Project/Area Number: 24501306
• Research Category: Grant-in-Aid for Scientific Research (C)
• Allocation Type: Multi-year Fund
• Section: 一般
• Research Field: Carcinogenesis
• Research Institution: Juntendo University
• Principal Investigator: TABE Yoko 順天堂大学, 医学部, 准教授 (70306968)
• Co-Investigator(Kenkyū-buntansha): IWABUCHI Kazuhisa 順天堂大学, 看護学部, 教授 (10184897) ; SASAI Keisuke 順天堂大学, 医学部, 教授 (20225858) ; 金 林花 順天堂大学, 医学(系)研究科(研究院), 研究員 (90531955)
• Project Period (FY): 2012-04-01 – 2015-03-31
• Project Status: Completed (Fiscal Year 2014)
• Budget Amount: ¥5,330,000 (Direct Cost: ¥4,100,000、Indirect Cost: ¥1,230,000); Fiscal Year 2014: ¥1,300,000 (Direct Cost: ¥1,000,000、Indirect Cost: ¥300,000); Fiscal Year 2013: ¥1,690,000 (Direct Cost: ¥1,300,000、Indirect Cost: ¥390,000); Fiscal Year 2012: ¥2,340,000 (Direct Cost: ¥1,800,000、Indirect Cost: ¥540,000)
• Keywords: 低線量放射線 / 微小環境 / 前がん細胞 / microRNA / プロテオミクス / miRNA / 骨髄微小環境 / 間質細胞 / アポトーシス

Outline of Final Research Achievements

Exposure to low-dose ionizing radiation (LDIR) can alter mammalian cell gene expression. We compared the cellular response of irradiated immortalized, EB virus;infected, B-cells (EBV-B) cultured alone with that of EBV-B cells co-cultured with bone marrow derived stromal cells (MSCs). The miRNAs let7a, miR-15b, miR-16, miR-21 and a lipid metabolic miRNA hub miR-23b were upregulated after LDIR exposure in the mono-cultured EBV-B cells, but were downregulated in EBV-B cells co-irradiated with MSCs. A lipid biosynthesis enzyme GPAM, the common target of these miRNAs, was downregulated at the level of protein and mRNA expression in the LDIR exposed mono-cultured EBV-B cells and upregulated MSCs co-cultured EBV-B cells, suggesting a putative novel miRNA regulatory mechanism in the genetic control of the LDIR-induced stress response. These findings illustrate that LDIR exposure and the cell’s microenvironment can affect specific gene expression, resulting in altered protein expression.

Research Products

• [Journal Article] Role of microenvironment in resistance to therapy in AML. (2015)
  • Author(s): Tabe Y, Konopleva M.
  • Journal Title: Current Hematologic Malignancy Reports Volume: in press
  • Peer Reviewed
• [Journal Article] Induction of p53-mediated transcription and apoptosis by Exportin-1 (XPO1) inhibition in mantle cell lymphoma. (2014)
  • Author(s): 4.Yoshimura M, Ishizawa J, Ruvolo V, Dilip A, Quintas-Cardama A, McDonnell TJ, Neelapu SS, Kwak LW, Shacham S, Kauffman M, Tabe Y, Yokoo M, Kimura S, Andreeff M, Kojima K
  • Journal Title: Cancer Sci. Volume: 105 Issue: 7 Pages: 795-801
  • DOI: 10.1111/cas.12430
  • Peer Reviewed
• [Journal Article] Therapeutic targeting of microenvironmental interactions in leukemia: mechanisms and approaches (2014)
  • Author(s): Tabe Y
  • Journal Title: Juntendo Medical Journal Volume: 60 Pages: 156-160
• [Journal Article] Class IA PI3K inhibition inhibits cell growth and proliferation in mantle cell lymphoma. (2014)
  • Author(s): Tabe Y, Jin L, Konopleva M, Shikami M, Kimura S, Andreeff M, Raffeld M, Miida T.
  • Journal Title: Acta Haematol. Volume: 131 Issue: 1 Pages: 59-69
  • DOI: 10.1159/000353164
  • Peer Reviewed
• [Journal Article] ICSH guidelines for the verification and performance of automated cell counters for body fluids. (2014)
  • Author(s): Bourner G, De la Salle B, George T, Tabe Y, Baum H, Culp N, Keng TB
  • Journal Title: Int J Lab Hematol. Volume: in press Issue: 6 Pages: 598-612
  • DOI: 10.1111/ijlh.12196
  • Peer Reviewed
• [Journal Article] Rivaroxaban attenuates leukocyte adhesion in the microvasculature and thrombus formation in an experimental mouse model of type 2 diabetes mellitus. (2014)
  • Author(s): Iba T, Aihara K, Yamada A, Nagayama M, Tabe Y, Ohsaka A.
  • Journal Title: Thromb Res. Volume: 133 Issue: 2 Pages: 276-280
  • DOI: 10.1016/j.thromres.2013.11.013
  • Peer Reviewed
• [Journal Article] Advances in understanding the leukaemia microenvironment. (2014)
  • Author(s): Tabe Y, Konopleva M.
  • Journal Title: Br J Haematol. Volume: 164 Issue: 6 Pages: 767-778
  • DOI: 10.1111/bjh.12725
  • Peer Reviewed
• [Journal Article] TGF-β-neutralizing antibody 1D11 enhances cytarabine-induced apoptosis in AML cells in the bone marrow microenvironment. (2013)
  • Author(s): Tabe Y, Shi YX, Zeng Z, Jin L, Shikami M, Hatanaka Y, Miida T, Hsu FJ, Andreeff M, Konopleva M.
  • Journal Title: PLoS One Volume: ８
  • Peer Reviewed
• [Journal Article] PI3K inhibitor GDC-0941 enhances apoptotic effects of BH-3 mimetic ABT-737 in AML cells in the hypoxic bone marrow microenvironment. (2013)
  • Author(s): Jin L, Tabe Y, Kojima K, Shikami M, Benito J, Ruvolo V, Wang RY, McQueen T, Ciurea SO, Miida T,
  • Journal Title: Mol Med (Berl) Volume: 91 Issue: 12 Pages: 1383-1397
  • DOI: 10.1007/s00109-013-1076-3
  • Peer Reviewed
• [Journal Article] Performance evaluation of the automated morphological analysis of erythrocytes by CellaVision DM96. (2013)
  • Author(s): Maenou I, Tabe Y, Bengtsson HI, Ishii K, Miyake K, Horiuchi Y, Idei M, Horii T, Satoh N, Miida T,
  • Journal Title: Clin Lab. Volume: 59 Pages: 1413-1417
  • Peer Reviewed
• [Journal Article] Meropenem as predictive risk factor for isolation of multidrug-resistant Pseudomonas aeruginosa. (2013)
  • Author(s): Nakamura A, Miyake K, Misawa S, Kuno Y, Horii T, Kondo S, Tabe Y, Ohsaka A
  • Journal Title: J Hosp Infect Volume: 83 Issue: 2 Pages: 153-155
  • DOI: 10.1016/j.jhin.2012.10.005
  • Peer Reviewed
• [Journal Article] Neutrophil extracellular traps, damage-associated molecular (2013)
  • Author(s): Iba T, Murai M, Nagaoka I, Tabe Y.
  • Journal Title: Acute Medicine & Surgery Volume: in press
  • Peer Reviewed
• [Journal Article] TGF-β-neutralizing antibody 1D11 enhances cytarabine-induced apoptosis in AML cells in the bone marrow microenvironment. (2013)
  • Author(s): Yoko Tabe, Yue Xi Shi, Zhihong Zeng, Linhua Jin, Masato Shikami,Yasuhito Hatanaka, Takashi Miida, Frank J. Hsu, Michael Andreeff, Marina Konopleva
  • Journal Title: PLOS ONE Volume: in press
  • Peer Reviewed
• [Journal Article] Mechanisms of apoptosis induction by simultaneous inhibition of PI3K and FLT3-ITD in AML cells in the hypoxic bone marrow microenvironment. (2012)
  • Author(s): Jin L, Tabe Y, Lu H, Borthakur G, Miida T, Kantarjian H, Andreeff M, Konopleva M.
  • Journal Title: Cancer Lett Volume: 329 Issue: 1 Pages: 45-58
  • DOI: 10.1016/j.canlet.2012.09.020
  • Peer Reviewed
• [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 RY, Ichikawa N, Miida T, Cortes J, Andreeff M, Konopleva M.
  • Journal Title: Leukemia Volume: 26 Issue: 5 Pages: 883-892
  • DOI: 10.1038/leu.2011.291
  • Peer Reviewed
• [Journal Article] Effects of PPARγ Ligands on Leukemia. (2012)
  • Author(s): Tabe Y, Konopleva M, Andreeff M, Ohsaka A.
  • Journal Title: PPAR Res. Volume: なし Pages: 1-8
  • DOI: 10.1155/2012/483656
  • Peer Reviewed
• [Presentation] The mTOR kinase inhibitor AZD-2014 effectively reverses XPO1/CRM1 antagonist KPT-185–induced glycolysis / gluconeogenesis, enhancing antitumor effects in mantle cell lymphoma. (2014)
  • Author(s): Yoko Tabe, Masako Harada, Yuka Miyamae, Hiromichi Matsushita, Kensuke Kojima, Tsutomu Fujimura, Saiko Kazuno, Takashi Ueno, Takashi Miida, Marina Konopleva, Michael Andreeff
  • Organizer: 56th American Society of Hematology Annual Meeting
  • Place of Presentation: San Francisco,USA
  • Year and Date: 2014-12-06 – 2014-12-09
• [Presentation] Metabolic re-programming in Notch-activated T-ALL by mTOR inhibitor AZD2014 combined with L-Asparaginase. (2014)
  • Author(s): Yoko Tabe, Masako Harada, Yuka Miyamae, Tsutomu Fujimura, Saiko Kazuno, Takashi Ueno, Takashi Miida, Michael Andreeff, Marina Konopleva.
  • Organizer: 56th American Society of Hematology Annual Meeting
  • Place of Presentation: San Francisco,USA
  • Year and Date: 2014-12-06 – 2014-12-09
• [Presentation] Pro-survival effects of TGF-β1 are associated with molecular signaling changes of ERK, FLI-1, and CD44 in AML cells. (2014)
  • Author(s): Yoko Tabe, Yasuhito Hatanaka, Peter Ruvolo, Takashi Miida, Steve Kornblau, Michael Andreeff, Marina Konopleva.
  • Organizer: 56th American Society of Hematology Annual Meeting
  • Place of Presentation: San Francisco,USA
  • Year and Date: 2014-12-06 – 2014-12-09
• [Presentation] Bone marrow adipocyte-derived free fatty acids induce gene signature linking transcription with metabolic changes that contribute to survival of acute monocytic leukemia cells (2014)
  • Author(s): Yoko Tabe, Masako Harada, Yuka Miyamae, Kaoru Mogushi, Saiko Kazuno, Tsutomu Fujimura, Hiromichi Matsushita, Takashi Ueno, Takehiko Yokomizo, Takashi Miida, Ismael Samudio, Michael Andreeff, Marina Konopleva.
  • Organizer: 56th American Society of Hematology Annual Meeting
  • Place of Presentation: San Francisco,USA
  • Year and Date: 2014-12-06 – 2014-12-09
• [Presentation] Selective inhibitor of nuclear export selinexor (KPT-330) and BCL2 inhibitor ABT-199 enhance the anti-lymphoma effect of BTK inhibitor ibrutinib in mantle cell lymphoma. (2014)
  • Author(s): Yoko Tabe, Masako Harada, Yuka Miyamae, Saiko Kazuno, Tsutomu Fujimura, Takashi Ueno, Takashi Miida, Marina Konopleva, Michael Andreeff
  • Organizer: 56th American Society of Hematology Annual Meeting
  • Place of Presentation: San Francisco,USA
  • Year and Date: 2014-12-06 – 2014-12-09
• [Presentation] Molecular mechanisms of inhibition of ribosomal biogenesis and translational flux by the Selective Inhibitor of Nuclear Export (SINE) XPO1/CRM1 antagonist KPT-185 in mantle cell lymphoma (2014)
  • Author(s): Yoko Tabe, Kensuke Kojima, Linhua Jin, Hiroko Iwanami, Hiromichi Matsushita, Saiko Kazuno, Michael Kauffman, Sharon Shacham, Tsutomu Fujimura, Takashi Ueno, Takashi Miida, Michael Andreeff
  • Organizer: Global Academic Programs 2014 Annual Conference
  • Place of Presentation: Soule, Korea
  • Year and Date: 2014-05-01 – 2014-05-03
• [Presentation] Molecular mechanisms of inhibition of ribosomal biogenesis and translational flux by the Selective Inhibitor of Nuclear Export (SINE) XPO1/CRM1 antagonist KPT-185 in mantle cell lymphoma. (2013)
  • Author(s): Tabe Y, Kojima K, Jin L, Iwanami H, Matsushita H, Kazuno S, Kauffman M, Shacham S, Fujimura T,
  • Organizer: 55th American Society of Hematology Annual Meeting
  • Place of Presentation: New Orleans,USA
• [Presentation] Integrative genomic and proteomic analysis of low-dose ionizing irradiation effects on bone marrow stromal microenvironment and on survival of pre-leukemic cells. (2013)
  • Author(s): Tabe Y, Jin L, Hatanaka Y, Matsushita H, Kazuno S, Fujimura T, Ueno T, Sasai K, Iwabuchi K, Andreeff M, Konopleva M, Miida T
  • Organizer: 55th American Society of Hematology Annual Meeting
  • Place of Presentation: New Orleans,USA
• [Presentation] Efficacy and mechanisms of the mTOR inhibitor AZD2014 combined with L-Asparaginase or JAK2 inhibitor TG101348 in ALL. (2013)
  • Author(s): Tabe Y, Jin L, Iwanami H, Matsushita H, Kazuno S, Fujimura T, Ueno T, Miida T, Weinstock D, Thomas DA, Andreeff M, Konopleva M.
  • Organizer: 55th American Society of Hematology Annual Meeting
  • Place of Presentation: New Orleans,USA
• [Presentation] Metabolic shift in hypoxia-adapted CML cells and mechanisms of acquired dasatinib resistance uncovered by proteomic iTRAQ profiling. (2013)
  • Author(s): Tabe Y, Jin L, Iwanami H, Matsushita H, Kazuno S, Fujimura T, Ueno T, Miida T, Andreeff M, Konopleva M, Kimura S.
  • Organizer: 55th American Society of Hematology Annual Meeting
  • Place of Presentation: New Orleans,USA
• [Presentation] Molecular mechanisms of adipocyte-leukemia interactions revealed by the quantitative proteomics technology: pro-survival function of adipocyte-derived free fatty acids on acute monoblastic leukemia mitochondrial biogenesis. (2013)
  • Author(s): Tabe Y, Jin L, Kazuno S, Fujimura T, Matsushita H, Ueno T, Miida T, Andreeff M, Konopleva M.
  • Organizer: 55th American Society of Hematology Annual Meeting
  • Place of Presentation: New Orleans,USA
• [Presentation] Efficacy of the internet-based e-leaning system using the CellaVision Competency Software for continuing professional development. (2013)
  • Author(s): Tabe Y, Ishii K, Kasuga K, Maenoh I, Horii T, Miida T, Ohsaka A.
  • Organizer: 26th International Symposium on Technological Innovations in Laboratory Hematology.
  • Place of Presentation: Toronto, Canada
• [Presentation] Performance evaluation of a novel high-risk Human Papilloma Virus Genotyping test (Clinichip HPV™). (2013)
  • Author(s): Yamada H, Tabe Y, Ishii K, Terao Y, Takeda S, Horii T, Ohsaka A.
  • Organizer: American Association for Clinical Chemistry Annual Meeting.
  • Place of Presentation: Houston, USA
• [Presentation] Detection of tumor cells in body fluids by the automated morphological analysis system CellaVision DM96 following the automated cell counting by the Sysmex XE5000. (2013)
  • Author(s): Takemura H, Tabe Y, Yamaguchi K, Ishii K, Kasuga K, Horii T, Miida T, Ohsaka A.
  • Organizer: American Association for Clinical Chemistry Annual Meeting
  • Place of Presentation: Houston, USA
• [Presentation] The clinical significance of mesothelial cell in peritoneal dialysis effluent detected by Cellavision DM96. (2013)
  • Author(s): Idei M, Tabe Y, Miyake K, Hamada C, Takemura H, Io H, Ishii K, Horii T, Tomino Y, Ohsaka A, Miida T.
  • Organizer: American Association for Clinical Chemistry Annual Meeting
  • Place of Presentation: Houston, USA
• [Presentation] TGF-beta1 Supports Leukemia Cell Survival Via Negative Regulation of FLI-1 Transcription Factor, ERK Inactivation and MMP-1 Secretion. (2012)
  • Author(s): Yoko Tabe, Linhua Jin, Yasuhito Hatanaka, Takashi Miida, Steven Kornblau, Michaell Andreeff, Marina Konopleva.
  • Organizer: American Society of Hematology Annual Meeting
  • Place of Presentation: Atlanta,USA
• [Presentation] Molecular Mechanisms of Antitumor Activity of the Selective Inhibitor of Nuclear Export (SINE) CRM1 Antagonist KPT-185 in Mantle Cell Lymphoma. (2012)
  • Author(s): Yoko Tabe, Kensuke Kojima, Linhua Jin, Takashi Miida, Shacham S, Kauffman M, Michaell Andreeff.
  • Organizer: American Society of Hematology Annual Meeting
  • Place of Presentation: Atlanta,USA
• [Presentation] Analysis of Dasatinib-Induced Molecular Mechanisms of Apoptosis in Hypoxia-Adopted CML Cells Utilizing Quantitative Proteomics Technology. (2012)
  • Author(s): Yoko Tabe, Linhua Jin, Hiroko Iwanami, Kazuno S, Fujimura T, Hiromichi Matsushita, Takashi Ueno, Takashi Miida, Michaell Andreeff, Marina Konopleva, Shinya Kimura.
  • Organizer: American Society of Hematology Annual Meeting
  • Place of Presentation: Atlanta,USA
• [Presentation] Molecular Mechanisms of Pro-Survival and Differentiating Function of Bone Marrow-Derived Adipocytes On Acute Monoblastic Leukemia Cells. (2012)
  • Author(s): Linhua Jin, Marina Konopleva, Masato Shikami, Takako Ikegami, Kensuke Kojima , MichaellAndreeff, Takashi Miida, Yoko Tabe
  • Organizer: American Society of Hematology Annual Meeting
  • Place of Presentation: Atlanta,USA
• [Presentation] 低線量放射線被爆による生体微小環境内の発がん誘導機序． (2012)
  • Author(s): 田部 陽子, 金 林花, 畑中 康人, 松下 弘道, 笹井 啓資, 三井田 孝
  • Organizer: 放射線影響学会
  • Place of Presentation: 仙台
• [Book] WBC differentiation Procedures (2012)
  • Author(s): Yoko Tabe, Naotake Satoh, Chiaki Tanaka
  • Total Pages: 69
  • Publisher: Sysmex corporation scientic affairs
• [Remarks] 順天堂大学医学部 臨床検査医学講座 【業績】
  • URL: http://www.juntendo.ac.jp/med/labo/rinsyo_byori3.html