論文 - 服部　豊

Immunomodulatory Effect of Proteasome Inhibitors via the Induction of Immunogenic Cell Death in Myeloma Cells.

Matsushita M, Kashiwazaki S, Kamiko S, Kobori M, Osada M, Kunieda H, Hirao M, Ichikawa D, Hattori Y

Pharmaceuticals (Basel, Switzerland) 16 （ 10 ）  2023年09月

ISSN  1424-8247

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GTN057, a komaroviquinone derivative, induced myeloma cells' death in vivo and inhibited c-MET tyrosine kinase

Okayama M., Fujimori K., Sato M., Samata K., Kurita K., Sugiyama H., Suto Y., Iwasaki G., Yamada T., Kiuchi F., Ichikawa D., Matsushita M., Hirao M., Kunieda H., Yamazaki K., Hattori Y.

Cancer Medicine （Cancer Medicine）  12 （ 8 ） 9749 - 9759 2023年04月

　概要を見る

Objective: Despite the development of newly developed drugs, most multiple myeloma (MM) patients with high-risk cytogenetic abnormalities such as t(4;14) or del17p relapse at anin early stage of their clinical course. We previously reported that a natural product,komaroviquinone (KQN), isolated from the perennial semi-shrub Dracocephalum komarovi, i.e., komaroviquinone (KQN) and its derivative GTN024 induced the apoptosis of MM cells by producing reactive oxygen species (ROS), but both exhibited significant hematological toxicity. Aim of this study is to clarify anti-tumor activity, safety and pharmacokinetics of GTN057, an optimization compound of KQN in vivo. Methods: ICR/SCID xenograft model of KMS11, a t(4;14) translocation-positive MM cell line, was used for in vivo study. Mice pharmacokinetics of GTN057 and the degradation products were analyzed by LC-MS/MS. Results: Herein, our in vitro experiments revealed that GTN057 is much less toxic to normal hematopoietic cells, induced the apoptosis of both MM cell lines andpatient samples, including those with high-risk cytogenetic changes. A xenograft model of a high-risk MM cell line demonstrated that GTN057 significantly delayed the tumor growth with no apparent hematological or systemic toxicities in vivo. The pathological examination of GTN057-treated tumors in vivoshowed revealed apoptosis of MM cells and anti-angiogenesis. In addition to the production of ROS, GTN057 inhibited the downstream signaling of c-MET, a receptor tyrosine kinase a receptor forand hepatocyte growth factor (HGF) receptor. Thus, GTN057 is less toxic and is able tomay be a candidate drug for treating MM patients, via multifunctional mechanisms. We have also extensively studied the pharmacologyical analysis of GTN057. The metabolites of GTN057, (e.g.,such as GTN054), may also have anti-tumorantitumor activity. Conclusion: Natural products or and their derivatives can could be good sources of antineoplastic drugs even for high-risk cancer.

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A thermoresponsive cationic block copolymer brush-grafted silica bead interface for temperature-modulated separation of adipose-derived stem cells

Nagase K., Okada A., Matsuda J., Ichikawa D., Hattori Y., Kanazawa H.

Colloids and Surfaces B: Biointerfaces （Colloids and Surfaces B: Biointerfaces）  220   112928 2022年12月

ISSN  09277765

　概要を見る

Adipose-derived mesenchymal stem cells (ADSCs) have beneficial effects in cell transplantation therapy; these cells are collected from adipose tissue using low-invasive methods. However, to prepare ADSCs for cell therapy, a cell separation method that neither involves modification of the cell surface nor causes loss of cell activity is needed. Here, we aimed to develop ADSC separation columns using thermoresponsive cationic block copolymer brush-grafted beads as packing materials. The block copolymer brush was formed by a bottom cationic segment, poly(N,N-dimethylaminopropylacrylamide) (PDMAPAAm), and an upper thermoresponsive segment, poly(N-isopropylacrylamide) (PNIPAAm), and was grafted in two atom transfer radical polymerization reactions. The copolymer brush-grafted silica beads were packed into a column. An ADSC suspension was introduced into the columns at 37 °C and adsorbed on the copolymer brush-modified beads through electrostatic and hydrophobic interactions with the PDMAPAAm and PNIPAAm segments, respectively. The adsorbed ADSCs eluted from the column by lowering the temperature to 4 °C. In contrast, most Jurkat and vascular endothelial cells eluted at 37 °C, because of the relatively weaker electrostatic interactions with the block copolymer brush compared to ADSCs. Using the prepared column, a mixture of ADSCs and Jurkat cells was separated by changing the column temperature. The recovered ADSCs exhibited cell activity. The developed cell separation column may be useful for isolating ADSCs without cell surface modification, while maintaining cell activity.

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初診時に著明な「リンパ球増多症」を呈したPAX5陽性形質細胞性白血病

舘野涼香、平尾磨樹、菊池隆秀、塚田唯子、國枝尚子、長田眞、山崎皓平、傳田竜之介、廣瀬茂道、松下麻衣子、市川大樹、服部豊

臨床血液 （日本血液学会）  63 （ 10 ） 1415 - 1420 2022年10月

研究論文（学術雑誌）, 共著, 最終著者, 責任著者, 査読有り,  ISSN  0485-1439

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Negative E-cadherin expression on bone marrow myeloma cell membranes is associated with extramedullary disease

Hirao M., Hattori Y., Yamazaki K., Watanabe K., Mukai K., Hirose S., Osada M., Tsukada Y., Kunieda H., Denda R., Kikuchi T., Sugimori H., Okamoto S.

F1000Research （F1000Research）  11   245 - 245 2022年02月

研究論文（学術雑誌）, 共著, 最終著者, 責任著者, 査読有り,  ISSN  20461402

　概要を見る

Background: The loss of E-cadherin expression and the induction of N-cadherin are known as hallmarks of the epithelial-to-mesenchymal transition, an essential initial step in the process of metastasis in solid tumors. Although several studies have reported expressions of these cadherins in patients with multiple myeloma (MM), their clinical significance is unknown as MM cells are non-epithelial. Methods: In this study, we examined the expression of E- and N-cadherins by immunohistochemistry using bone marrow (BM) biopsy specimens from 31 newly diagnosed MM patients and in subsequent biopsy specimens from six of these. Results: Negative E-cadherin expression on BM myeloma cell membranes was significantly associated with the presence of soft-tissue masses arising from bone lesions and breaking through the cortical bone, referred to as extramedullary disease (EMD). Conclusions: Given the aggressive nature of EMD, our study suggests that screening for E-cadherin using BM immunohistochemistry is one measure that could predict the development of EMD in patients with MM.

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Integrin β5 and β7 expression in lenalidomide-resistant multiple myeloma cells

Yutaka Hattori · Takumi Futo · Ryo Uozaki · Daiju Ichikawa · Takashi Yamaguchi · Tomofumi Yamamoto · Maiko Matsushita · Maki Hirao

International Journal of Hematology （Springer Nature）  2022年02月

研究論文（学術雑誌）, 共著, 査読有り

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SORT1/LAMP2-mediated Extracellular Vesicle Secretion and Cell Adhesion Are Linked to Lenalidomide Resistance in Multiple Myeloma

Tomofumi Yamamoto, Jun Nakayama, Yusuke Yamamoto, Masahiko Kuroda, Yutaka Hattori, Takahiro Ochiya

Blood Advance （American Society of Hematology）  2022年01月

研究論文（学術雑誌）, 査読有り

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Thermally-modulated cell separation columns using a thermoresponsive block copolymer brush as a packing material for the purification of mesenchymal stem cells

Nagase K., Edatsune G., Nagata Y., Matsuda J., Ichikawa D., Yamada S., Hattori Y., Kanazawa H.

Biomaterials Science （Biomaterials Science）  9 （ 21 ） 7054 - 7064 2021年11月

研究論文（学術雑誌）, 共著, 査読有り,  ISSN  20474830

　概要を見る

Cell therapy using mesenchymal stem cells (MSCs) is used as effective regenerative treatment. Cell therapy requires effective cell separation without cell modification and cellular activity reduction. In this study, we developed a temperature-modulated mesenchymal stem cell separation column. A temperature-responsive cationic block copolymer, poly(N,N-dimethylaminopropylacrylamide)-b-poly(N-isopropylacrylamide)(PDMAPAAm-b-PNIPAAm) brush with various cationic copolymer compositions, was grafted onto silica beads via two-step atom transfer radical polymerization. Using the packed beads, the elution behavior of the MSCs was observed. At 37 °C, the MSCs were adsorbed onto the column via both hydrophobic and electrostatic interactions with the PNIPAAm and PDMAPAAm segments of the copolymer brush, respectively. By reducing the temperature to 4 °C, the adsorbed MSCs were eluted from the column by reducing the hydrophobic and electrostatic interactions attributed to the hydration and extension of the PNIPAAm segment of the block copolymer brush. From the temperature-modulated adsorption and elution behavior of MSCs, a suitable DMAPAAm composition of the block copolymer brush was determined. Using the column, a mixture of MSC and BM-CD34+ cells was separated by simply changing the column temperature. The column was used to purify the MSCs, with purities of 78.2%, via a temperature change from 37 °C to 4 °C. Additionally, the cellular activity of the MSCs was retained throughout the column separation step. Overall, the obtained results show that the developed column is useful for MSC separation without cell modification and cellular activity reduction. This journal is

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Antibody drug separation using thermoresponsive anionic polymer brush modified beads with optimised electrostatic and hydrophobic interactions

Nagase K, Ishii S, Ikeda K, Yamada S, Ichikawa D, Akimoto A.M, Hattori Y, Kanazawa H

Scientific Reports （Nature Research）  10 （ 1 ）  2020年12月

研究論文（学術雑誌）, 共著, 査読有り

　概要を見る

© 2020, The Author(s). Antibody drugs play an important role in biopharmaceuticals, because of the specificity for target biomolecules and reduction of side effects. Thus, separation and analysis techniques for these antibody drugs have increased in importance. In the present study, we develop functional chromatography matrices for antibody drug separation and analysis. Three types of polymers, poly(N-isopropylacrylamide (NIPAAm)-co-2-acrylamido-2-methylpropanesulfonic acid (AMPS)-co-N-phenyl acrylamide (PhAAm)), P(NIPAAm-co-AMPS-co-n-butyl methacrylate (BMA)), and P(NIPAAm-co-AMPS-co-tert-butylacrylamide (tBAAm)), were modified on silica beads through atom transfer radical polymerisation. Rituximab elution profiles were observed using the prepared beads-packed column. Rituximab adsorption at high temperature and elution at low temperature from the column were observed, as a result of the temperature-modulated electrostatic and hydrophobic interactions. Using the column, rituximab purification from contaminants was performed simply by changing the temperature. Additionally, three types of antibody drugs were separated using the column through temperature-modulated hydrophobic and electrostatic interactions. These results demonstrate that the temperature-responsive column can be applied for the separation and analysis of biopharmaceuticals through a simple control of the column temperature.

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Characteristics of a novel target antigen against myeloma cells for immunotherapy

Matsushita M, Saito S, Yokoe S, Ichikawa D, Hattori Y

Vaccines （MDPI）  8 （ 4 ） 1 - 13 2020年12月

研究論文（学術雑誌）, 共著, 査読有り

　概要を見る

© 2020 by the authors. Licensee MDPI, Basel, Switzerland. Despite the availability of therapeutic treatments, multiple myeloma is an incurable haematological disorder. In this study, we aimed to clarify the role of CXorf48 as a therapeutic target in multiple myeloma. Based on a previously identified HLA-A*24:02-restiricted epitope from this novel cancer/testis antigen, we characterized the activities of cytotoxic T lymphocytes (CTLs) specific to this antigen against myeloma cells and evaluated the effects of demethylating agents in increasing antigen expression and enhancing the cytotoxic activity of CTLs. CXorf48 expression was examined by reverse transcription polymerase chain reaction (RT-PCR) using nine myeloma cell lines. Cell lines with low CXorf48 expression were treated by demethylating agents (DMAs), 5-azacytidine (5-aza), and 5-aza-2'-deoxycytidine (DAC) to evaluate gene expression using quantitative RT-PCR. Furthermore, CXorf48-specific CTLs were induced from peripheral blood mononuclear cells of HLA-A*24:02-positive healthy donors to evaluate antigen recognition using ELISpot and51 Cr cytotoxicity assays. CXorf48 was widely expressed in myeloma cells, and gene expression was significantly increased by DMAs. Furthermore, CXorf48-specific CTLs recognized DMA-treated myeloma cells. These findings suggest that CXorf48 is a useful target for immunotherapy, such as vaccination, in combination with demethylating agents for the treatment of patients with myeloma.

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A phenylphthalimide derivative, TC11, induces apoptosis by degrading MCL1 in multiple myeloma cells

Ichikawa D, Nakamura M, Murota W, Osawa S, Matsushita M, Yanagawa H, Hattori Y

Biochemical and Biophysical Research Communications （Elsevier）  521 （ 1 ） 252 - 258 2020年01月

研究論文（学術雑誌）, 共著, 査読有り,  ISSN  0006291X

　概要を見る

© 2019 To date, the prognosis of multiple myeloma (MM) in patients harboring cytogenetic abnormalities (CA) involving t (4; 14) and deletion of chromosome 17 remains poor despite recent advances in drug development that include the use of immunomodulatory drugs (IMiDs) such as lenalidomide for MM. To address this issue, we have developed a novel phenylphthalimide derivative, TC11, that is structurally related to IMiDs. It remains unclear how TC11 induces apoptosis of MM cells with high-risk CA. Here, we show that TC11 does not induce degradation of CRBN's substrates, IKZF1/3 and CK1α, and induces apoptosis of CRBN-silenced MM; this effect was independent of the cereblon (CRBN) pathway, which is involved in the mechanism of action of IMiDs used for the treatment of MM. We also revealed that TC11, in contrast to existing IMiDs, induced degradation of MCL1 and activation of caspase-9. Furthermore, inhibition of CDK1 by CGP74514A prevented TC11-induced MCL1 degradation, caspase-9 activation, and the subsequent apoptotic cell death. We showed that ectopic MCL1 expression rescued apoptosis of MM. These observations suggest that TC11 induces apoptotic death caused by degradation of MCL1 during prolonged mitotic arrest. Therefore, our findings suggest that TC11 is a potential drug candidate for high-risk MM.

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Significance of peripheral mononuclear cells producing interferon-γ in response to insulin B:9–23-related peptides in subtypes of type 1 diabetes

Oikawa Y, Sakamoto K, Satomura A, Haisa A, Katsuki T, Hattori Y, Inoue I, Noda M, Shimada A

Clinical Immunology （Clinical Immunology）  208 （ Nov ） 108260 - 108260 2019年11月

研究論文（学術雑誌）, 共著, 査読有り,  ISSN  15216616

　概要を見る

© 2019 Elsevier Inc. Type 1 diabetes is largely caused by β-cell destruction through anti-islet autoimmunity. Reportedly, interferon (IFN)-γ-secreting peripheral blood mononuclear cells (PBMCs) specific to four insulin B-chain amino acid 9–23-related peptides (B:9–23rPep) were increased in type 1 diabetes participants. This study aimed to investigate the PBMC frequencies in subtypes of type 1 diabetes using enzyme-linked immunospot assay. In this cross-sectional study, peripheral blood samples were obtained from 148 participants including 72 with acute-onset type 1 diabetes (AT1D), 51 with slowly progressive insulin-dependent diabetes mellitus (SPIDDM), and 25 with type 2 diabetes. The frequency of B:9–23rPep-specific IFN-γ-producing PBMCs was significantly higher in AT1D participants than in SPIDDM and type 2 diabetes participants. Meanwhile, a significant inverse correlation was observed between the PMBC frequencies and insulin secretion capacity in SPIDDM participants. These findings suggest that the increased peripheral B:9–23rPep-specific IFN-γ immunoreactivity reflects decreased functional β-cell mass and greater disease activity of type 1 diabetes.

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Temperature-modulated cell-separation column using temperature-responsive cationic copolymer hydrogel-modified silica beads

Nagase K, Inanaga D, Ichikawa D, Mizutani Akimoto A, Hattori Y, Kanazawa H

Colloids and Surfaces B: Biointerfaces （Elsevier）  178   253 - 262 2019年06月

研究論文（学術雑誌）, 共著, 査読有り,  ISSN  09277765

　概要を見る

© 2019 Elsevier B.V. There is strong demand for cell separation methods that do not decrease cell activity or modify cell surfaces. Here, new temperature-modulated cell-separation columns not requiring cell-surface premodification are described. The columns were packed with temperature-responsive cationic polymer hydrogel-modified silica beads. Poly(N-isopropylacrylamide-co-n-butyl methacrylate-co-N,N-dimethylaminopropyl acrylamide) hydrogels with various cationic moieties were attached to silica-bead surfaces by radical polymerization using N,Nʹ-methylenebisacrylamide as a crosslinking agent. The beads were packed into solid-phase extraction columns, and temperature-dependent cell elution from the columns was found using HL-60 and Jurkat cells. The retention HL-60 and Jurkat cells in columns containing cationic beads at 37 °C was 95.3% to 99.6% and 95.0% to 98.8%, respectively. By contrast, beads without cationic properties exhibited low cell retention (20.6% for HL-60 and 32.5% for Jurkat cells). The cells were mainly retained through both electrostatic and hydrophobic interactions. The retained HL-60 (4.9%) and Jurkat cells (40%) were eluted at 4 °C from the column with a low composition of cationic monomer (DMAPAAm, 1 mol% in copolymer), because the temperature-responsive hydrogels on the beads became hydrophilic, decreasing the hydrophobic interactions between the cells and the beads. A higher number of Jurkat cells than HL-60 cells were eluted because of differences in their electrostatic properties (Jurkat cells: −2.53 mV; HL-60 cells: −20.7 mV). The results indicated that cell retention by the hydrogel-coated beads packed in a solid phase extraction column could be modulated simply by changing the temperature.

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A novel derivative (GTN024) from a natural product, komaroviquinone, induced the apoptosis of high-risk myeloma cells via reactive oxygen production and ER stress

Okayama M., Kitabatake S., Sato M., Fujimori K., Ichikawa D., Matsushita M., Suto Y., Iwasaki G., Yamada T., Kiuchi F., Hirao M., Kunieda H., Osada M., Okamoto S., Hattori Y.

Biochemical and Biophysical Research Communications （Elsevier）  505 （ 3 ） 787 - 793 2018年10月

研究論文（学術雑誌）, 共著, 査読有り,  ISSN  0006291X

　概要を見る

© 2018 Elsevier Inc. New drugs have significantly improved the survival of patients with multiple myeloma (MM), but the prognosis of MM patients with high-risk cytogenetic changes such as t(4; 14), t(14; 16) or del17p remains very poor. A natural product, komaroviquinone (KQN), was originally isolated from the perennial semi-shrub Dracocephalum komarovi and has anti-protozoal activity against Trypanosoma cruzi, the organism causing Chagas’ disease. Here we demonstrate that a novel KQN-derivative, GTN024, has an anti-MM effect both in vitro and in vivo. GTN024 induced the apoptosis of MM cell lines including those with high-risk cytogenetic changes. GTN024 produced reactive oxygen species (ROS) and increased phosphorylated eIF2α. The ROS production and subsequent endoplasmic reticulum (ER) stress are thought to play a key role in GTN024-induced apoptosis, as the apoptosis was completely abrogated by anti-oxidant treatment. In a mouse xenograft model, an intraperitoneal injection of 20 mg/kg of GTN024 significantly delayed tumor growth. Hematological toxicity and systemic toxicity as indicated by weight loss were not observed. These results suggest that the novel KQN-derivative GTN024 could become a candidate drug for treating high-risk MM.

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A challenge to aging society by microRNA in extracellular vesicles: MicroRNA in extracellular vesicles as promising biomarkers and novel therapeutic targets in multiple myeloma

Yamamoto T., Kosaka N., Hattori Y., Ochiya T.

Journal of Clinical Medicine （MDPI）  7 （ 3 ）  2018年03月

研究論文（学術雑誌）, 共著

　概要を見る

Multiple myeloma (MM) is a malignancy of terminally differentiated plasma cells and is the second most common hematological cancer. MM frequently occurs in the elderly population with the median age as the middle sixties. Over the last 10 years, the prognosis of MM has been dramatically improved by new therapeutic drugs; however, MM is still incurable. The pathogenesis of MM is still unclear, thus greater understanding of the molecular mechanisms of MM malignancy is desirable. Recently, microRNAs (miRNAs) were shown to modulate the expression of genes critical for MM pathogenesis. In addition, miRNAs are secreted via extracellular vesicles (EVs), which are released from various cell types including MM cells, and these miRNAs are involved in multiple types of cell-cell interactions, which lead to the malignancy of MM. In this review, we summarize the current knowledge regarding the role of miRNA secretion via EVs and of EVs themselves in MM development. We also discuss the potential clinical applications of EVs as promising biomarkers and new therapeutic targets for improving the outcome of MM, resulting in a brighter future for aging societies.

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A novel phenylphthalimide derivative, pegylated TC11, improves pharmacokinetic properties and induces apoptosis of high-risk myeloma cells via G2/M cell-cycle arrest.

Aida S, Hozumi M, Ichikawa D, Iida K, Yonemura Y, Tabata N, Yamada T, Matsushita M, Sugai T, Yanagawa H, Hattori Y

Biochem. Biophysic. Res. Commun. （Elsevier）  493 （ 1 ） 514 - 520 2017年09月

研究論文（学術雑誌）, 共著, 査読有り,  ISSN  0006-291X

　概要を見る

Despite the development of new drugs for multiple myeloma (MM), the prognosis of MM patients with high-risk cytogenetic abnormalities such as t (4; 14) and del17p remains poor. We reported that a novel phenylphthalimide derivative, TC11, induced apoptosis of MM cells in vitro and in vivo, and TC11 directly bound to a-tubulin and nucleophosmin-1 (NPM1). However, TC11 showed low water solubility and poor pharmacokinetic properties. Here we synthesized a water-soluble TC11-derivative, PEG(E)-TC11, in which HOEtO-TC11 is pegylated with PEG through an ester bond, and we examined its anti-myeloma activity. We observed that PEG(E)-TC11 and its hydrolyzed product, HOEtO-TC11, induced G2/M arrest and the apoptosis of MM cells. Intraperitoneal administration of PEG(E)-TC11 to xenografted mice revealed improved pharmacokinetic properties and significantly delayed tumor growth. TC11 and its derivatives did not bind to cereblon (CRBN), which is a responsible molecule for thalidomide-induced teratogenicity. These results suggest that PEG(E)-TC11 is a good candidate drug for treating high-risk MM.

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Synthesis and biological evaluation of the natural product komaroviquinone and related compounds aiming at a potential therapeutic lead compound for high-risk multiple myeloma.

Suto Y, Sato M, Fujimori K, Kitabatake S, Okayama M, Ichikawa D, Matsushita M, Yamagiwa N, Iwasaki G, Kiuchi F, Hattori Y.

Bioorganic & Medicinal Chemistry Letters （Elsevier）  27 （ 19 ） 4558 - 4563 2017年

研究論文（学術雑誌）, 共著, 査読有り,  ISSN  0960-894X

　概要を見る

Alternatives of treatments for multiple myeloma (MM) have become increasingly available with the advent of new drugs such as proteasome inhibitors, thalidomide derivatives, histone deacetylase inhibitors, and antibody drugs. However, high-risk MM cases that are refractory to novel drugs remain, and further optimization of chemotherapeutics is urgently needed.
We had achieved asymmetric total synthesis of komaroviquinone, which is a natural product from the plant Dracocephalum komarovi. Similar to several leading antitumor agents that have been developed from natural compounds, we describe the antitumor activity and cytotoxicity of komaroviquinone and related compounds in bone marrow cells. Our data suggested that komaroviquinone-related agents have potential as starting compounds for anticancer drug development. (C) 2017 Elsevier Ltd. All rights reserved.

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CXorf48 is a potential therapeutic target for achieving treatment-free remission in CML patients

Matsushita M, Ozawa K, Suzuki T, Nakamura M, Nakano N, Kanchi S, Ichikawa D, Matsuki E, Sakurai M, Karigane D, Kasahara H, Tsukamoto N, Shimizu T, Mori T, Nakajima H, Okamoto S, Kawakami Y, Hattori Y

Blood Cancer J （Springer Nature）  7   e701 2017年

研究論文（学術雑誌）, 共著, 査読有り

Identification of novel HLA-A*24:02-restricted epitope derived from a homeobox protein expressed in hematological malignancies.

服部 豊

PLoS One 11 （ 1 ） e0146371 2016年01月

研究論文（学術雑誌）, 共著, 査読有り

A novel phthalimide derivative, TC11, has preclinical effects on high-risk myeloma cells and osteoclasts.

Matsushita M, Yoshie Ozaki Y, Hasegawa Y, Terada F, Tabata N, Shiheido H, Yanagawa H, Oikawa T, Matsuo K, Du W, Yamada T, Hozumi M, Ichikawa D, Hattori Y

PLoS One 10 （ 1 ） e0116135 2015年01月

研究論文（学術雑誌）, 共著, 査読有り

多発性骨髄腫におけるCD138陽性細胞比率が低下することの臨床的意義

井上 純子, 池田 昌弘, 新垣 清登, 宮崎 寛至, 飯塚 聡介, 阿部 有, 関根 理恵子, 塚田 信弘, 服部 豊, 鈴木 憲史

臨床血液 （日本血液学会）  56 （ 11 ） 2311 - 2317 2015年

研究論文（学術雑誌）, 共著, 査読有り,  ISSN  0485-1439

　概要を見る

骨髄腫細胞はCD138を強発現すると考えられてきたが，一部の症例で骨髄腫細胞中のCD138⁺細胞比率の低下が確認される。本研究は，診断時CD138⁺細胞比率が50%以上を占めていた患者において，治療経過中にCD138⁺細胞比率が低下した群（12名）とCD138⁺細胞比率が維持していた群（105名）に分類し，CD138⁺細胞比率が低下することの臨床的意義を検討した。この2群間で全生存期間に有意差はなく，低下群において観察期間中に死亡した9名(75%)のCD138⁺細胞比率の低下確認後の生存期間は中央値25ヶ月と比較的短期間であり，すべてが腫瘍死であった。死亡例の内，7例はCD138⁺細胞比率が低下した状態で死亡していた。一方，生存例3例の内，2例で治療後CD138⁺細胞比率の再上昇が見られた。低下群においてCD138⁺細胞比率の低下後に，一部の症例では髄外病変や予後不良な細胞遺伝学的異常［del(17p), t(4;14), c-MYCの増幅］が検出された。以上より，CD138⁺細胞比率の低下は骨髄腫細胞の更なる悪性形質の獲得と関係があることが示唆された。CD138⁺細胞比率の低下が予後や薬剤耐性に寄与する因子であるかは不明だが，治療で比率の改善が見られない場合には予後は短期間となる可能性がある。

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IMiDsの作用機序と催奇形性

服部 豊

腫瘍内科 （科学評論社）  14 （ 6 ） 596 - 600 2014年12月

単著

Detection of leukemia associated antigen-specific cytotoxic T cells in a patient with Philadelphia chromosome-positive leukemia during treatment with dasatinib.

Matsushita M, Tonegawa K, Mori T, Kohashi S, Kato J, Matsuki E, Okamoto S, Hattori Y.

Leukemia Lymphoma （INFORMA HEALTHCARE）  55 （ 3 ） 722 - 724 2014年03月

研究論文（学術雑誌）, 共著, 査読有り,  ISSN  1042-8194

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IMWG consensus on risk stratification in multiple myeloma.

4. Chng WJ, Dispenzieri A, Chim CS, Fonseca R, Goldschmidt H, Lentzsch S, Munshi N, Palumbo A, Miguel JS, Sonneveld P, Cavo M, Usmani S, Durie BG, Avet-Loiseau H; International Myeloma Working Group (Hattori Y, et al.).

Leukemia （NATURE PUBLISHING GROUP）  28 （ 2 ） 269 - 277 2014年02月

共著,  ISSN  0887-6924

　概要を見る

Multiple myeloma is characterized by underlying clinical and biological heterogeneity, which translates to variable response to treatment and outcome. With the recent increase in treatment armamentarium and the projected further increase in approved therapeutic agents in the coming years, the issue of having some mechanism to dissect this heterogeneity and rationally apply treatment is coming to the fore. A number of robustly validated prognostic markers have been identified and the use of these markers in stratifying patients into different risk groups has been proposed. In this consensus statement, the International Myeloma Working Group propose well-defined and easily applicable risk categories based on current available information and suggests the use of this set of prognostic factors as gold standards in all clinical trials and form the basis of subsequent development of more complex prognostic system or better prognostic factors. At the same time, these risk categories serve as a framework to rationalize the use of therapies.

• Access to Document (DOI)

Codon 72 Polymorphism of TP53 Gene Is a Novel Prognostic Marker for Thalidomide Therapy in Multiple Myeloma.

Hattori Y, Ikeda Y, Suzuki Y, Ichikawa D, Matsushita M.

British Journal of Haematology 165 （ 5 ） 728 - 731 2014年01月

研究論文（学術雑誌）, 共著, 査読有り

多発性骨髄腫に対する新規薬剤の二次性骨髄異形成症候群・急性白血病発症への影響

濱野愛里、新垣清登、阿部有、宮崎寛至、関根理恵子、中川靖章、塚田信弘、服部　豊、鈴木憲史

臨床血液 （日本血液学会）  55 （ 4 ） 428 - 435 2014年

研究論文（学術雑誌）, 共著

Codon 72 polymorphism of TP53 gene is a novel prognostic marker for therapy in multiple myeloma

Yutaka Hattori, Yurika Ikeda, Yuya Suzuki, Daiju Ichikawa, Maiko Matsushita

British Journal of Haematology （Blackwell Publishing Ltd）  165 （ 5 ） 728 - 731 2014年

査読有り,  ISSN  1365-2141

• Access to Document (DOI)

A Myeloma Cell Line Established from a Patient Refractory to Thalidomide Therapy Revealed High-Risk Cytogenetic Abnormalities and Produced Vascular Endothelial Growth Factor.

Hattori Y, Du W, Yamada T, Ichikawa D, Matsunami S, Matsushita M

Blood Cancer J 3   e115 2013年05月

研究論文（学術雑誌）, 共著

Plasma cell leukemia: consensus statement on diagnostic requirements, response criteria and treatment recommendations by the International Myeloma Working Group.

服部 豊

Leukemia （NATURE PUBLISHING GROUP）  27 （ 4 ） 780 - 791 2013年

研究論文（学術雑誌）, 共著, 査読有り,  ISSN  0887-6924

　概要を見る

Plasma cell leukemia (PCL) is a rare and aggressive variant of myeloma characterized by the presence of circulating plasma cells. It is classified as either primary PCL occurring at diagnosis or as secondary PCL in patients with relapsed/refractory myeloma. Primary PCL is a distinct clinic-pathological entity with different cytogenetic and molecular findings. The clinical course is aggressive with short remissions and survival duration. The diagnosis is based upon the percentage (>= 20%) and absolute number (>= 2 x 10(9)/l) of plasma cells in the peripheral blood. It is proposed that the thresholds for diagnosis be re-examined and consensus recommendations are made for diagnosis, as well as, response and progression criteria. Induction therapy needs to begin promptly and have high clinical activity leading to rapid disease control in an effort to minimize the risk of early death. Intensive chemotherapy regimens and bortezomib-based regimens are recommended followed by high-dose therapy with autologous stem cell transplantation if feasible. Allogeneic transplantation can be considered in younger patients. Prospective multicenter studies are required to provide revised definitions and better understanding of the pathogenesis of PCL. Leukemia (2013) 27, 780-791; doi:10.1038/leu.2012.336

• Access to Document (DOI)

Post-transplant consolidation therapy using thalidomide alone for the patients with multiple myeloma: a feasibility study in Japanese population.

Ueda T, Iino R, Yokoyama K, Okamoto S, Asakura K, Tsukada Y, Ishizawa J, Matsuki E, Ikeda Y, Hattori Y

Int J Hematol 96   477-484 2012年10月

研究論文（学術雑誌）, 共著

An Anilinoquinazoline Derivative Inhibits Tumor Growth through Interaction with hCAP-G2, a Subunit of Condensin II.

Shiheido H, Naito Y, Kimura H, Genma H, Takashima H, Tokunaga M, Ono T, Hirano T, Du W, Yamada T, Doi N, Iijima S, Hattori Y, Yanagawa H

PLoS One 7(9)   e44889 2012年09月

研究論文（学術雑誌）, 共著

A Phthalimide Derivative that is Effective on Multiple Myeloma Inhibits Centrosomal Clustering by Interacting with Nucleophosmin.

Shiheido H, Terada F, Tabata N, Ichigo Hayakawa I, Matsumura N, Takashima H, Ogawa Y, Du W, Yamada T, Shoji M, Sugai T, Doi N, Iijima S, Hattori Y, Yanagawa H

PLOS One 7(6)   e38878 2012年06月

研究論文（学術雑誌）, 共著

Isoelectric focusing of urinary transferrin for detection of early stages of diabetic nephropathy.

Sakai N, Kubota R, Shiba K, Hattori Y, Iijima S

J Electrophoresis 56   1-6 2012年03月

研究論文（学術雑誌）, 共著

自家造血幹細胞移植5年後にB細胞性急性リンパ性白血病を発症した多発性骨髄腫.

塚田唯子、服部 豊、中島秀明、横山健次、村田満、清水長子、近藤直美、岡本真一郎.

臨床血液 53(2)   219-223 2012年02月

研究論文（学術雑誌）, 共著

Risk of progression and survival in multiple myeloma relapsing after therapy with IMiDs and bortezomib: a multicenter international myeloma working group study.

Kumar SK, ほか International, Myeloma Working Group, Hattori Y

Leukemia 26(1)   149-157 2012年01月

研究論文（学術雑誌）, 共著

Bortezomibとアゾール系抗真菌薬の併用後に短期間で麻痺性腸閉塞を発症した多発性骨髄腫.

甲田 祐也, 森 毅彦, 清水 隆之, 加藤 淳, 山根 明子, 定平 健, 塚田 唯子, 横山 健次, 橋本 典諭, 服部 豊, 岡本 真一郎

臨床血液 （日本血液学会）  53 （ 8 ） 760 - 764 2012年

研究論文（学術雑誌）, 共著, 査読有り,  ISSN  0485-1439

Efficacy of Long-Term Treatment with Low-Dose Thalidomide for Patients with Relapsed/Refractory Multiple Myeloma.

Shimizu K, Murakami H, Sawamura M, Hattori Y, Okamoto S, Miwa A, Sugiura I, Shimazaki C, Taniwaki M, Ishida T, Hayashi T, Kosugi H, Yuge M, Iida S, Ishida T, Sunami K, Asaoku H, Sakai A, Abe M, Takagi T

International Journal of Clinical Medicine 2   570-575 2011年10月

研究論文（学術雑誌）, 共著, 査読有り

Prospective Study of Combination Therapy with Low-Dose Thalidomide plus Prednisolone Ameliorating Cytopenia in Primary Myelofibrosis.

Hattori Y, Miyakawa Y, Yokoyama K, Yamada T, Du W, Jinzaki M, Shinmoto H, Okamoto S

Int J Hematol 93   129-131 2011年01月

研究論文（学術雑誌）, 共著

Production of a reactive metabolite of troglitazone by electrochemical oxidation performed in nonaqueous medium.

Tahara K, Nishikawa T, Hattori Y, Iijima S, Kouno Y, Abe Y

J Pharm Biomed Anal 50   1030-1036 2009年12月

研究論文（学術雑誌）, 共著

International myeloma working group (IMWG) consensus statement and guidelines regarding the current status of stem cell collection and high-dose therapy for multiple myeloma and the role of plerixafor (AMD 3100).

Giralt S ほかInternational, Myeloma Working Group, Hattori Y

Leukemia 23(10)   1904-1912 2009年10月

研究論文（学術雑誌）, 共著

多発性骨髄腫とボルテゾミブ.

定平 健, 服部 豊.

日本医師会雑誌 138(4)   734-735 2009年07月

研究論文（学術雑誌）, 共著

The role of vertebral augmentation in multiple myeloma: International Myeloma Working Group Consensus Statement.

Hussein MA et, al, International Myeloma Working Group, Hattori Y

Leukemia 22(8)   1479-1484 2008年08月

研究論文（学術雑誌）, 共著

Single-Institute Phase 2 Study of Thalidomide Treatment for Refractory or Relapsed Multiple Myeloma:Prognostic Factors and Unique Toxicity Profile.

Hattori Y, Okamoto S, Shimada N, Kakimoto T, Morita K, Tanigawa Y, Ikeda Y

Cancer Sience 99   1243-1250 2008年06月

研究論文（学術雑誌）, 共著

多発性骨髄腫における肝細胞増殖因子(HGF)の予後因子としての意義と分子標的療法.

○服部豊, 井口豊崇, 岡本真一郎, 島田直樹, 杜ぶん林, 山田健人, 松本邦夫, 中村敏一, 佐川森彦, 大槻剛巳, 池田康夫.

臨床血液 49   359-366 2008年06月

研究論文（学術雑誌）, 共著

多発性骨髄腫における肝細胞増殖因子(HGF)の分子標的療法の有用性.

服部豊.

血液・腫瘍科 （科学評論社）  56   581-588 2008年05月

単著

NK4, an antagonist of hepatocyte growth factor (HGF), inhibits growth of multiple myeloma cells in vivo; molecular targeting of angiogenic growth factor.

Du W, Hattori Y, Yamada T, Matsumoto K, Nakamura T, Sagawa M, Otsuki T, Niikura T, Nukiwa T, Ikeda Y

Blood 109   3042-3049 2007年04月

研究論文（学術雑誌）, 共著

Recurrence of autoimmune disease after autologous peripheral blood stem cell transplantation for multiple myeloma.

Isshiki I, Okamoto S, Kakimoto T, Chen CK, Mori T, Yokoyama K, Hattori Y, Ikeda Y

Int J Hematol 84   354-358 2006年06月

研究論文（学術雑誌）, 共著

Thalidomide for the treatment of leptomeningeal multiple myeloma.

Hattori Yutaka, Yabe Mariko, Okamoto Shinichiro, Morita Kunihiko, Tanigawara Yusuke, Ikeda Yasuo

European Journal of Hematology 76   358-359 2006年02月

研究論文（学術雑誌）, 共著

サリドマイドと多発性骨髄腫

服部 豊

感染・炎症・免疫 35 （ 2 ） 178-181 2005年06月

研究論文（学術雑誌）, 単著

Pulmonary hypertension and thalidomide therapy in multiple myeloma.

Hattori Yutaka, Shimoda M, Okamoto Shinichiro, Satoh T, Kakimoto Tsunayuki, Ikeda Yasuo

British Journal of Haematology 128   885-887 2005年03月

研究論文（学術雑誌）, 共著

Thalidomide for the treatment of multiple myeloma.

Hattori Yutaka, Iguchi Toyotaka

Congenital Anomalies 44   125-136 2004年10月

研究論文（学術雑誌）, 共著

骨髄腫に対するサリドマイド療法の現状．

服部 豊

血液フロンティア 14 （ 10 ） 1545-1554 2004年10月

研究論文（学術雑誌）, 単著

Gene therapy targeting hematopoietic stem cells.

服部 豊

Frontiers in Immuno-gene Therapy    91-110 2004年05月

研究論文（学術雑誌）, 共著

Tumor angiogenesis in the bone marrow of multiple myeloma patients and its alteration by thalidomide treatment.

Du Wenlin, Hattori Yutaka, Hashiguchi Akinori, Kondoh Kensuke, Hozumi Nobumichi, Ikeda Yasuo, Sakamoto Michiie, Hata Jun-ichi, Yamada Taketo

Pathology International 54 （ 5 ） 285-294 2004年05月

研究論文（学術雑誌）, 共著

Thalidomide-induced severe neutropenia during treatment of multiple myeloma.

Hattori Yutaka, Kakimoto Tsunayuki, Okamoto Shinichiro, Sato Norihide, Ikeda Yasuo

International Journal of Hematology 79 （ 3 ） 283-288 2004年03月

研究論文（学術雑誌）, 共著

IgD myeloma with systemic amyloidosis with chest discomfort as an initial symptom.

服部 豊

Keio J Med 53   178 - 190 2004年

研究論文（学術雑誌）, 共著, 査読有り

多発性骨髄腫におけるサリドマイドの有効性，問題点と今後．

柿本　綱之，　服部 豊

医薬ジャーナル 39 （ 8 ） 2257-2261 2003年08月

研究論文（学術雑誌）, 共著

サリドマイドの臨床応用：多発性骨髄腫に対するサリドマイドの臨床応用の実際

服部 豊

血液フロンティア 13 （ 7 ） 901-910 2003年07月

研究論文（学術雑誌）, 単著

多発性骨髄腫に対するサリドマイド治療．

柿本　綱之，　服部 豊

医学のあゆみ別冊：造血器腫瘍のあらたな治療戦略    75-78 2003年06月

研究論文（学術雑誌）, 共著

Anti-c-Mpl (thrombopoietin receptor) autoantibody-induced amegakaryocytic thrombocytopenia in a patient with systemic sclerosis.

Katsumata Yasuhiro, Suzuki Takahiro, Kuwana Masataka, Hattori Yutaka, Akizuki Satoshi, Sugiura Hitoshi, Matsuoka Yasuo

Arthritis & Rheumatism 48 （ 6 ） 1647-1651 2003年06月

研究論文（学術雑誌）, 共著

Thalidomideを用いた多発性骨髄腫の治療．

服部 豊

臨床血液 44 （ 5 ） 302-312 2003年05月

研究論文（学術雑誌）, 単著

抗骨髄腫薬としてのサリドマイドの復活：現状と問題点

木崎 昌弘，　服部　豊

Front Wave in Hematology 5   39179 2003年05月

研究論文（学術雑誌）, 共著

Bone marrow angiogenesis and anti-angiogenic therapy in multiple myeloma

Hattori Yutaka

Internal medicine 42 （ 3 ） 303-305 2003年03月

研究論文（学術雑誌）, 単著

多発性骨髄腫と血管新生

佐藤範英，服部豊

血管医学 3 （ 6 ） 613-620 2002年12月

研究論文（学術雑誌）, 共著

多発性骨髄腫と血管新生

服部豊

日本内科学会雑誌 91 （ 臨時増刊号 ） 121-126 2002年09月

研究論文（学術雑誌）, 単著

Thalidomide for the treatment of refractory multiple myeloma: association of plasma concentrations of thalidomide and angiogenic growth factors with clinical outcome

Kakimoto Tsunayuki, Hattori Yutaka, Okamoto Shinichiro, Sato Norihide, Kamata Tamihiro, Yamaguchi Masaya, Morita Kunihiko, Yamada Taketo, Takayama Nobuyuki, Uchida Hideo, Shimada Naoki, Tanigawara Yusuke, Ikeda Yasuo

Japanese journal of cancer research 93 （ 9 ） 1029-1036 2002年09月

研究論文（学術雑誌）, 共著

サリドマイドによる不応性多発性骨髄腫の治療

柿本綱之，服部豊，岡本真一郎

臨床血液 43 （ 5 ） 345-348 2002年05月

研究論文（学術雑誌）, 共著

Elevated level of plasma basic fibroblast growth factor in multiple myeloma correlates with increased disease activity

Sato Norihide, Hattori Yutaka, Wenlin Du, Yamada Taketo, Kamata Tamihiro, Kakimoto Tsunayuki, Okamoto Shinichiro, Kawamura Chiharu, Kizaki Masahiro, Shimada Naoki, Ote Yukiko, Hata Jun-ichi, Ikeda Yasuo

Japanese journal of cancer research 93 （ 5 ） 459-466 2002年04月

研究論文（学術雑誌）, 共著

Elevated level of plasma basic fibroblast growth factor in multiple myeloma correlates with increased disease activity

Sato Norihide, Hattori Yutaka, Wenlin Du, Yamada Taketo, Kamata Tamihiro, Kakimoto Tsunayuki, Okamoto Shinichiro, Kawamura Chiharu, Kizaki Masahiro, Shimada Naoki, Ote Yukiko, Hata Jun-ichi, Ikeda Yasuo

Japanese journal of cancer research 93 （ 4 ） 459-466 2002年04月

研究論文（学術雑誌）, 共著

Keratinocyte growth factor regulates proliferation and differentiation of hematopoietic cells expressing the receptor gene K-sam

Kamata Tamihiro, Hattori Yutaka, Hamada Hirofumi, Kizaki Masahiro, Terada Masaaki, Ikeda Yasuo

Experimental hematology 30 （ 5 ） 297-305 2002年04月

研究論文（学術雑誌）, 共著

Keratinocyte growth factor regulates proliferation and differentiation of hematopoietic cells expressing the receptor gene K-<i>sam</i>

Kamata Tamihiro, Hattori Yutaka, Hamada Hirofumi, Kizaki Masahiro, Terada Masaaki, Ikeda Yasuo

Experimental hematology 30 （ 5 ） 297-305 2002年04月

兄弟間に発症したfollicular lymphoma

朝日厚子，岡本真一郎，松下弘道，服部豊，高山信之，池田康夫

臨床血液 42 （ 5 ） 408-413 2001年05月

研究論文（学術雑誌）, 共著

造血器腫瘍における骨髄腫瘍血管新生

鎌田民弘，服部豊，佐藤範英，柿本綱之

臨床検査 44 （ 13 ） 1646-1648 2000年12月

研究論文（学術雑誌）, 共著

Bone morphogenetic protein-2 induces apoptosis in human myeloma cells with modulation of STAT3

Kawamura Chiharu, Kizaki Masahiro, Yamato Kenji, Uchida Hideo, Fukuchi Yumi, Hattori Yutaka, Koseki Takeyoshi, Nishihara Tatsuji, Ikeda Yasuo

Blood 96 （ 6 ） 2005-2011 2000年09月

研究論文（学術雑誌）, 共著

多発性骨髄腫における骨髄腫瘍血管新生─病態の解明と新しい治療法の開発

服部豊，柿本綱之

臨床血液 41 （ 5 ） 426-429 2000年08月

研究論文（学術雑誌）, 共著

治療抵抗性多発性骨髄腫におけるサリドマイドの有効性

服部豊，柿本綱之

血液・腫瘍科 41 （ 2 ） 120-127 2000年08月

研究論文（学術雑誌）, 共著

サリドマイドを使った多発性骨髄腫治療

服部豊，岡本真一郎，柿本綱之，池田康夫

Hematological Malignancy Review 13   5-6 2000年06月

研究論文（学術雑誌）, 共著

A patient with genetic deletion of glutathione-S-transferase T1 and M1 who developed non-small-cell lung cancer and myelodysplastic syndromes

Arai Yasumichi, Hirose Nobuyoshi, Yamamura Ken, Nagai Maiko, Jang Hong, Hattori Yutaka, Ikeda Yasuo

American Journal of the Medical Sciences 318 （ 6 ） 424-427 1999年12月

研究論文（学術雑誌）, 共著

十二指腸に原発し，節外再発を繰り返したNatural killer-like T cell lymphoma

都築泰彦，岡本真一郎，高山信之，鎌田民弘，服部豊，川合陽子，木崎昌弘，池田康夫

臨床血液 40 （ 6 ） 494-498 1999年06月

研究論文（学術雑誌）, 共著

12指腸に原発し，節外再発を繰り返したNatural killer-like T-cell

都築泰彦，岡本真一郎，高山信之，鎌田民弘，服部豊，川合陽子，木崎昌弘，池田康夫

臨床血液 40 （ 6 ） 494-498 1999年

研究論文（学術雑誌）, 共著

Restoration of retinoid sensitivity by MDR1 ribozymes in retinoic acid-resistant myeloid leukemic cells

Matsushita Hiromichi, Kizaki Masahiro, Kobayashi Hiroyuki, Ueno Hironori, Muto Akihiro, Takayama Nobuyuki, Awaya Norihiro, Kinjo Kentaro, Hattori Yutaka, Ikeda Yasuo

Blood 91 （ 7 ） 2452-2458 1998年04月

研究論文（学術雑誌）, 共著

造血幹細胞への遺伝子導入とその応用

服部豊

臨検査 40 （ 8 ） 939-945 1996年08月

研究論文（学術雑誌）, 単著

Immunohistochemical detection of K-sam protein in stomach cancer

Hattori Yutaka, Itoh Hiroshi, Uchino Shinya, Hosokawa Kouichi, Ochiai Atsushi, Ino Yoshinori, Ishii Hideshi, Sakamoto Hiromi, Yamaguchi Naohito, Yanagihara Kazuyoshi, Hirohashi Setsuo, Sugimura Takashi, Terada Masaaki

Clin Cancer Res 2   1373-1381 1996年08月

研究論文（学術雑誌）, 共著

Decreased insulin-like growth factor I receptor expression and function in immortalized african Pygmy T cells

Hattori Yutaka, Vera Carlos Juan, Rivas I Coralia, Bersch Noelle, Bailey C Robert, Geffner E Mitchell, Golde W David

J Clin Endocrinol Metab 81 （ 6 ） 2257-2263 1996年

研究論文（学術雑誌）, 共著

Preferential alternative splicing in cancer generates a K-sam messenger RNA with higher transforming activity.

服部 豊

Cancer Research （AMER ASSOC CANCER RESEARCH）  54 （ 12 ） 3237 - 3241 1994年

研究論文（学術雑誌）, 共著, 査読有り,  ISSN  0008-5472

　概要を見る

K-sam, also designated fibroblast growth factor receptor 2/BEK, was originally cloned from a stomach cancer cell line KATO-III. The gene is amplified and overexpressed preferentially in poorly differentiated types of stomach cancers. The major K-sam transcript in KATO-III cells encodes a receptor protein with a truncated carboxyl terminus and with a high-affinity binding site for keratinocyte growth factor. This truncated type is produced by an alternative splicing mechanism, and in normal tissues, the truncated type is far less prevalent than the untruncated form. The variant K-sam complementary DNA lacks tyrosine 769, which is a putative phospholipase C gamma 1 association site, and showed a higher transforming activity to NIH3T3 cells than the untruncated form, which is identical with the keratinocyte growth factor receptor.

Preferential expression of the third immunoglobulin-like domain of K-sam product provides keratinocyte growth factor-dependent growth in carcinoma cell lines.

服部 豊

Cancer Research 54   518 - 522 1994年

研究論文（学術雑誌）, 共著, 査読有り

Isolation of the complementary DNA encoding a mouse heparin-binding growth factor receptor with the use of a unique kinase insert sequence.

服部 豊

Cancer Research （AMER ASSOC CANCER RESEARCH）  53 （ 5 ） 1136 - 1141 1993年

研究論文（学術雑誌）, 共著, 査読有り,  ISSN  0008-5472

　概要を見る

With the use of reverse transcriptase-polymerase chain reaction techniques focused on a unique kinase insert sequence, the complementary DNA for a mouse tyrosine kinase receptor gene, designated sam3, was isolated from a mouse brain complementary DNA library as a member of the heparin-binding growth factor receptor family or fibroblast growth factor receptor family. The kinase insert region was selected as the probe synthesized by polymerase chain reaction techniques because it composes a unique structure in this receptor family. The sam3 protein, 800 amino acids long, bas high homology to mouse K-sam/bek (67%) and N-sam/flg (63%), which we also cloned as the mouse counterparts of human K-sam/bek and N-sam/flg genes, other members of this family. The sam3 protein also has high homology to human FGFR3 (92%) and chicken cek2 (80%) proteins. The sam3 protein is most likely to be a mouse counterpart of human FGFR3 and chicken cek2 proteins. mRNAs of K-sam/bek, N-sam/flg, and sam3/FGFR3 genes were detected in mouse embryo through some adult tissues. The relative amounts of these mRNAs were different depending on the organs examined. Thus, these gene products may have different biological functions in organ development including the central nervous system.

K-sam-related gene, N-sam, encodes fibroblast growth factor receptor and is expressed in T-lymphocytic tumors.

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Cancer Research （AMER ASSOC CANCER RESEARCH）  52 （ 12 ） 3367 - 3371 1992年

研究論文（学術雑誌）, 共著, 査読有り,  ISSN  0008-5472

　概要を見る

We recently reported the isolation of the K-sam complementary DNA (cDNA), which was amplified preferentially in poorly differentiated types of stomach cancer and codes for one of the heparin-binding growth factor or fibroblast growth factor (FGF) receptor families. The K-sam-related gene, N-sam (NCC-IT-cell-derived sam), was isolated by screening of the cDNA libraries of human immature teratoma cells, NCC-IT. Sequence analysis of the N-sam cDNAs showed that N-sam encodes a human FGF receptor, the FLG protein. N-sam was expressed in lymphocytic leukemia/lymphoma cells, predominantly in the thymic T-cell phenotype. In a T-cell leukemia line, MOLT3, N-sam mRNA expression was markedly enhanced by 12-O-tetradecanoylphorbol-13-acetate treatment and was also up-regulated by basic FGF exposure. These results indicate that N-sam expression is regulated during T-cell ontogeny and modulated by its putative ligand exposure. The results also suggested that interaction between immature T-cell and marrow or thymic interstitial cells might be mediated by N-sam and basic FGF stored in the extracellular matrix of stromal cells.

K-sam gene encodes secreted as well as transmembrane receptor tyrosine kinase.

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Proc. Natl. Acad. Sci. USA 89   2960 - 2964 1992年

研究論文（学術雑誌）, 共著, 査読有り

Expression of the heparin-binding growth factor receptor genes in human megakaryocytic leukemia cells.

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Biochem. Biophys. Res. Commun. （ACADEMIC PRESS INC JNL-COMP SUBSCRIPTIONS）  183 （ 1 ） 83 - 92 1992年

研究論文（学術雑誌）, 共著, 査読有り,  ISSN  0006-291X

K-sam, an amplified gene in stomach cancer, is a member of the heparin-binding growth factor receptor genes.

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Proc. Natl. Acad. Sci. USA 87   5983 - 5987 1990年

研究論文（学術雑誌）, 共著, 査読有り