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Sakiko Satake,
Hideyo Hirai,
Yoshihiro Hayashi,
Nobuaki Shime,
Akihiro Tamura, Hisayuki Yao,
Satoshi Yoshioka,
Yasuo Miura,
Tohru Inaba,
Naohisa Fujita,
Eishi Ashihara,
Jiro Imanishi,
Teiji Sawa,
Taira Maekawa
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ABSTRACT: Granulopoiesis is tightly regulated to meet host demands during both "steady-state" and "emergency" situations, such as infections. The transcription factor CCAAT/enhancer binding protein β (C/EBPβ) plays critical roles in emergency granulopoiesis, but the precise developmental stages in which C/EBPβ is required are unknown. In this study, a novel flow cytometric method was developed that successfully dissected mouse bone marrow cells undergoing granulopoiesis into five distinct subpopulations (#1-5) according to their levels of c-Kit and Ly-6G expression. After the induction of candidemia, rapid mobilization of mature granulocytes and an increase in early granulocyte precursors accompanied by cell cycle acceleration was followed by a gradual increase in granulocytes originating from the immature populations. Upon infection, C/EBPβ was upregulated at the protein level in all the granulopoietic subpopulations. The rapid increase in immature subpopulations #1 and #2 observed in C/EBPβ knockout mice at 1 d postinfection was attenuated. Candidemia-induced cell cycle acceleration and proliferation of hematopoietic stem/progenitors were also impaired. Taken together, these data suggest that C/EBPβ is involved in the efficient amplification of early granulocyte precursors during candidemia-induced emergency granulopoiesis.
The Journal of Immunology 09/2012; 189(9):4546-55. · 5.79 Impact Factor
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Ruriko Tanaka,
Shinya Kimura,
Eishi Ashihara,
Mariko Yoshimura,
Naoto Takahashi,
Hisashi Wakita,
Kuniaki Itoh,
Kaichi Nishiwaki,
Kenshi Suzuki,
Rina Nagao, Hisayuki Yao,
Yoshihiro Hayashi,
Sakiko Satake,
Hideyo Hirai,
Ken-Ichi Sawada,
Oliver G Ottmann,
Junia V Melo,
Taira Maekawa
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ABSTRACT: ABL tyrosine kinase inhibitor (TKI), imatinib is used for BCR-ABL(+) leukemias. We developed an automatic method utilizing guanine-quenching probes (QP) to detect 17 kinds of mutations frequently observed in imatinib-resistance. Results were obtained from 100μL of whole blood within 90min by this method. Detected mutations were almost identical between QP method and direct sequencing. Furthermore, the mutation-biased PCR (MBP) was added to the QP method to increase sensitivity, resulting earlier detection of T315I mutation which was insensitive to any ABL TKIs. Thus, the QP and MBP-QP may become useful methods for the management of ABL TKI-treated patients.
Cancer letters 08/2011; 312(2):228-34. · 4.86 Impact Factor
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Rina Nagao,
Eishi Ashihara,
Shinya Kimura,
Jeffrey W Strovel, Hisayuki Yao,
Miki Takeuchi,
Ruriko Tanaka,
Yoshihiro Hayashi,
Hideyo Hirai,
Janak Padia,
Kathryn Strand,
Taira Maekawa
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ABSTRACT: We investigated the effect of a novel Wnt/β-catenin signaling inhibitor, AV65 on imatinib mesylate (IM)-sensitive and -resistant human chronic myeloid leukemia (CML) cells in vitro. AV65 inhibited the proliferation of various CML cell lines including T315I mutation-harboring cells. AV65 reduced the expression of β-catenin in CML cells, resulting in the induction of apoptosis. Moreover, AV65 inhibited the proliferation of hypoxia-adapted primitive CML cells that overexpress β-catenin. The combination of AV65 with IM had a synergistic inhibitory effect on the proliferation of CML cells. These findings suggest that AV65 could be a novel therapeutic agent for the treatment of CML.
Cancer letters 08/2011; 312(1):91-100. · 4.86 Impact Factor
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ABSTRACT: INTRODUCTION: The Wnt/β-catenin signaling pathway plays a pivotal role in the regulation of cell growth, cell development and the differentiation of normal stem cells. Constitutive activation of the Wnt/β-catenin signaling pathway is found in many human cancers, and is thus an attractive target for anti-cancer therapy. Specific inhibitors of this pathway have been keenly researched and developed. AREAS COVERED: This review discusses the potential of inhibiting the Wnt/β-catenin signaling pathway, as a therapeutic approach for cancer, along with an overview of the development of specific inhibitors. EXPERT OPINION: Cancer stem cells (CSCs) play a significant role in the development and recurrence of several cancers, and Wnt/β-catenin signaling is important for the proliferation of CSCs. Inhibition of Wnt/β-catenin signaling is therefore a promising treatment approach. Progress has been made in the development of screening methods to identify Wnt/β-catenin signaling inhibitors. Biomarker-based screening is an effective and promising method for the identification of compounds of interest.
Expert opinion on therapeutic targets 07/2011; 15(7):873-87. · 3.72 Impact Factor
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Miki Takeuchi,
Eishi Ashihara,
Yohko Yamazaki,
Shinya Kimura,
Yoko Nakagawa,
Ruriko Tanaka, Hisayuki Yao,
Rina Nagao,
Yoshihiro Hayashi,
Hideyo Hirai,
Taira Maekawa
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ABSTRACT: Treatment with Abl tyrosine kinase inhibitors (TKI) drastically improves the prognosis of chronic myelogenous leukemia (CML) patients. However, quiescent CML cells are insensitive to TKI and can lead to relapse of the disease. Thus, research is needed to elucidate the properties of these quiescent CML cells, including their microenvironment, in order to effectively target them. Hypoxia is known to be a common feature of solid tumors that contributes to therapeutic resistance. Leukemic cells are also able to survive and proliferate in severely hypoxic environments. The hypoxic conditions in the bone marrow (BM) allow leukemic cells that reside there to become insensitive to cell death stimuli. To target leukemic cells in hypoxic conditions, we focused on the hypoxia-selective cytotoxin, Rakicidin A. A previous report showed that Rakicidin A, a natural product produced by the Micromonospora strain, induced hypoxia-selective cytotoxicity in solid tumors. Here, we describe Rakicidin A-induced cell death in hypoxia-adapted (HA)-CML cells with stem cell-like characteristics. Interestingly, apoptosis was induced via caspase-dependent and -independent pathways. In addition, treatment with Rakicidin A in combination with the TKI, imatinib, resulted in synergistic cytotoxicity against HA-CML cells. In conclusion, Rakicidin A is a promising compound for targeting TKI-resistant quiescent CML stem cells in the hypoxic BM environment.
Cancer Science 03/2011; 102(3):591-6. · 3.33 Impact Factor
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Kazuki Sakai,
Eri Kawata,
Eishi Ashihara,
Yoko Nakagawa,
Akira Yamauchi, Hisayuki Yao,
Rina Nagao,
Ruriko Tanaka,
Asumi Yokota,
Miki Takeuchi,
Hideyo Hirai,
Shinya Kimura,
Mitsuomi Hirashima,
Norio Yoshimura,
Taira Maekawa
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ABSTRACT: Galectins comprise a family of animal lectins that differ in their affinity for β-galactosides. Galectin-9 (Gal-9) is a tandem-repeat-type galectin that was recently shown to function as a ligand for T-cell immunoglobin domain and mucin domain-3 (Tim-3) expressed on terminally differentiated CD4(+) Th1 cells. Gal-9 modulates immune reactions, including the induction of apoptosis in Th1 cells. In this study, we investigated the effects of Gal-9 in murine models of acute GVH disease (aGVHD). First, we demonstrated that recombinant human Gal-9 inhibit MLR in a dose-dependent manner, involving both Ca(2+) influx and apoptosis in T cells. Next, we revealed that recombinant human Gal-9 significantly inhibit the progression of aGVHD in murine BM transplantation models. In conclusion, Gal-9 ameliorates aGVHD, possibly by inducing T-cell apoptosis, suggesting that gal-9 may be an attractive candidate for the treatment of aGVHD.
European Journal of Immunology 01/2011; 41(1):67-75. · 5.10 Impact Factor
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Ruriko Tanaka,
Matthew S Squires,
Shinya Kimura,
Asumi Yokota,
Rina Nagao,
Takahiro Yamauchi,
Miki Takeuchi, Hisayuki Yao,
Matthias Reule,
Tomoko Smyth,
John F Lyons,
Neil T Thompson,
Eishi Ashihara,
Oliver G Ottmann,
Taira Maekawa
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ABSTRACT: Despite promising clinical results from imatinib mesylate and second-generation ABL tyrosine kinase inhibitors (TKIs) for most BCR-ABL(+) leukemia, BCR-ABL harboring the mutation of threonine 315 to isoleucine (BCR-ABL/T315I) is not targeted by any of these agents. We describe the in vitro and in vivo effects of AT9283 (1-cyclopropyl-3[5-morpholin-4yl methyl-1H-benzomidazol-2-yl]-urea), a potent inhibitor of several protein kinases, including Aurora A, Aurora B, Janus kinase 2 (JAK2), JAK3, and ABL on diverse imatinib-resistant BCR-ABL(+) cells. AT9283 showed potent antiproliferative activity on cells transformed by wild-type BCR-ABL and BCR-ABL/T315I. AT9283 inhibited proliferation in a panel of BaF3 and human BCR-ABL(+) cell lines both sensitive and resistant to imatinib because of a variety of mechanisms. In BCR-ABL(+) cells, we confirmed inhibition of substrates of both BCR-ABL (signal transducer and activator of transcription-5) and Aurora B (histone H3) at physiologically achievable concentrations. The in vivo effects of AT9283 were examined in several mouse models engrafted either subcutaneously or intravenously with BaF3/BCR-ABL, human BCR-ABL(+) cell lines, or primary patient samples expressing BCR-ABL/T315I or glutamic acid 255 to lysine, another imatinib-resistant mutation. These data together support further clinical investigation of AT9283 in patients with imatinib- and second-generation ABL TKI-resistant BCR-ABL(+) cells, including T315I.
Blood 09/2010; 116(12):2089-95. · 9.90 Impact Factor
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ABSTRACT: Bone marrow suppression after intensive chemotherapies in patients with myeloid leukemia is severe, resulting in the reduction of the number of white blood cells, red blood cells, and platelets. Supportive therapies are indispensable for the management of these leukemia patients. The improvement of blood cell transfusion can decrease side effects of chemotherapies and establish the safety. But we still have notable side effects of transfusion such as TRALI (transfusion-related acute lung injury), platelet immunologic refractory state, and so on. Cytokine therapy especially with G-CSF (granulocyte colony-stimulating factor) administration, changed the treatment of myeloid leukemia. G-CSF can shorten the duration of neutropenia and decrease the risk of infection. Recently the effects of Epo (erythropoietin) on chemotherapy-induced anemia have been demonstrated. We discuss here the indications of blood cell transfusion and cytokine therapies in the treatment for myeloid leukemia.
Nippon rinsho. Japanese journal of clinical medicine 10/2009; 67(10):1951-7.
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Asumi Yokota,
Shinya Kimura,
Ruriko Tanaka,
Miki Takeuchi, Hisayuki Yao,
Kazuki Sakai,
Rina Nagao,
Junya Kuroda,
Yuri Kamitsuji,
Eri Kawata,
Eishi Ashihara,
Taira Maekawa
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ABSTRACT: Osteoclasts (OCs) are specialized cells for the resorption of bone matrix that have also been recently reported to be involved in the mobilization of hematopoietic progenitor cells. When Ba/F3 cells expressing wild-type bcr-abl were co-cultured with osteoblasts (OBs), OCs, and bone slices, their proliferation was significantly suppressed, and the Ki-67 negative population, which is believed to be in G(0) phase, was increased. The results of our in vitro experiments suggest that OCs could be involved in the maintenance of dormant leukemic cells in the bone marrow (BM) microenvironment through the release of soluble factors, one of which could be TGF-beta.
Leukemia research 09/2009; 34(6):793-9. · 2.36 Impact Factor
