Molecular targeted therapy of hematological malignancies based on the genomic information

• Project/Area Number: 17019060
• Research Category: Grant-in-Aid for Scientific Research on Priority Areas
• Allocation Type: Single-year Grants
• Review Section: Biological Sciences
• Research Institution: Jichi Medical University
• Principal Investigator: MANO Hiroyuki Jichi Medical University, 医学部, 教授 (90240704)
• Co-Investigator(Kenkyū-buntansha): YAMASHITA Yoshihiro 自治医科大学, 医学部, 准教授 (10326861) ; OZAWA Kbiya (OZAWA Keiya) 自治医科大学, 医学部, 教授 (30137707)
• Project Period (FY): 2005 – 2009
• Project Status: Completed (Fiscal Year 2009)
• Budget Amount: ¥33,400,000 (Direct Cost: ¥33,400,000); Fiscal Year 2009: ¥6,700,000 (Direct Cost: ¥6,700,000); Fiscal Year 2008: ¥6,700,000 (Direct Cost: ¥6,700,000); Fiscal Year 2007: ¥6,700,000 (Direct Cost: ¥6,700,000); Fiscal Year 2006: ¥6,800,000 (Direct Cost: ¥6,800,000); Fiscal Year 2005: ¥6,500,000 (Direct Cost: ¥6,500,000)
• Keywords: acute mveloid leukemia / DNA microarray / gene expression profiling / リシークエンス / 急性骨髄性白血病 / マイクロRNA / DNAチップ / 網羅的清伝子発現解析 / 網羅的遺伝子発現解析

Research Abstract

In many of human leukemias, we still do not have effective molecular targeted therapies nor accurate diagnostic means. To address these issues, here we have purified and collected CD133-positive stem cell fractions from bone marrow of affected individuals, and applied a variety of genomics approaches toward such purified fractions. Through such screenings, we could construct a prediction scheme for patients' prognosis based on the expression level of the selected genes, and could identify novel oncogenes responsible for the development of acute myeloid leukemia.

Research Products

• [Journal Article] Array-based genomic resequencing of human leukemia (2010)
  • Author(s): Yamashita Y, Yuan J, Suetake I, Suzuki H, Ishikawa Y, Choi YL, Ueno T, Soda M, Hamada T, Haruta H, Takada S, Miyazaki Y, Kiyoi H, Ito E, Naoe T, Tomonaga M, Toyota M, Tajima S, Iwama A, Mano H.
  • Journal Title: Oncogene (in press)
  • Peer Reviewed
• [Journal Article] Tec protein tyrosine kinase inhibits CD25 expression in human T-lymphocyte (2010)
  • Author(s): Susaki K, Kitanaka A, Dobashi H, Kubota Y, Kittaka K, Kameda T, Yamaoka G, Mano H, Mihara K, Ishida T.
  • Journal Title: Immunol Lett 127 Pages: 135-142
  • Peer Reviewed
• [Journal Article] KIF5B-ALK, a novel fusion oncokinase identified by an immunohistochemistry-based diagnostic system for ALK-positive lung cancer (2009)
  • Author(s): Takeuchi K, Choi YL, Togashi Y, Soda M, Hatano S, Inamura K, Takada S, Ueno T, Yamashita Y, Satoh Y, Okumura S, Nakagawa K, Ishikawa Y, Mano H.
  • Journal Title: Clin Cancer Res 15 Pages: 3143-3149
  • Peer Reviewed
• [Journal Article] Potential role of miR-29b in modulation of Dnmt3a and Dnmt3b expression in primordial germ cells of female mouse embryos (2009)
  • Author(s): Takada S, Berezikov E, Choi YL, Yamashita Y, Mano H.
  • Journal Title: RNA 15 Pages: 1507-1514
  • Peer Reviewed
• [Journal Article] Schedule-dependent synergism and antagonism between pemetrexed and docetaxel in human lung cancer cell lines in vitro (2009)
  • Author(s): Kano Y, Tanaka M, Akutsu M, Mori K, Yazawa Y, Mano H, Furukawa Y.
  • Journal Title: Cancer Chemother Pharmacol 64 Pages: 1129-1137
  • Peer Reviewed
• [Journal Article] Genome-wide histone methylation profile for heart failure (2009)
  • Author(s): Kaneda R, Takada S, Yamashita Y, Choi YL, Nonaka-Sarukawa M, Soda M, Misawa Y, Isomura T, Shimada K, Mano H.
  • Journal Title: Genes Cells 14 Pages: 69-77
  • Peer Reviewed
• [Journal Article] KIFSB-ALK, a novel fusion oncokinase identified by an immunohistoche mistry-based diagnostic system for ALK-positive lung cancer (2009)
  • Author(s): Takeuchi K, et al.
  • Journal Title: Clin Cancer Res 15 Pages: 3143-3149
  • Peer Reviewed
• [Journal Article] EML4-ALK lung cancers are characterized by rare other mutations, a TTF-1 cell lineage, an acinar histology, and young onset (2009)
  • Author(s): Inamura K, et al.
  • Journal Title: Mod Pathol 22 Pages: 508-515
  • Peer Reviewed
• [Journal Article] Multiplex reverse transcription-PCR screening for EML4-ALK fusion transcripts (2008)
  • Author(s): Takeuchi K, Choi YL, Soda M, Inamura K, Togashi Y, Hatano S, Enomoto M, Takada S, Yamashita Y, Satoh Y, Okumura S, Nakagawa K, Ishikawa Y, Mano H.
  • Journal Title: Clin Cancer Res 14 Pages: 6618-6624
  • Peer Reviewed
• [Journal Article] MicroRNA expression profiles of human leukemias (2008)
  • Author(s): Takada S, Yamashita Y, Berezikov E, Hatanaka H, Fujiwara SI, Kurashina K, Watanabe H, Enomoto M, Soda M, Choi YL, Mano H.
  • Journal Title: Leukemia 22 Pages: 1274-1278
  • Peer Reviewed
• [Journal Article] A mouse model for EML4-ALK-positive lung cancer (2008)
  • Author(s): Soda M, Takada S, Takeuchi K, Choi YL, Enomoto M, Ueno T, Haruta H, Hamada T, Yamashita Y, Ishikawa Y, Sugiyama Y, Mano H.
  • Journal Title: Proc Natl Acad Sci U S A 105 Pages: 19893-19897
  • Peer Reviewed
• [Journal Article] Functional analysis of JAK3 mutations in transient myeloproliferative disorder and acute megakaryoblastic leukaemia accompanying Down syndrome" Br (2008)
  • Author(s): Sato T, Toki T, Kanezaki R, Xu G, Terui K, Kanegane H, Miura M, Adachi S, Migita M, Morinaga S, Nakano T, Endo M, Kojima S, Kiyoi H, Mano H, Ito E.
  • Journal Title: J Haematol 141 Pages: 681-688
  • Peer Reviewed
• [Journal Article] Non-solid oncogenes in solid tumors: EML4-ALK fusion genes in lung cancer (2008)
  • Author(s): Mano H.
  • Journal Title: Cancer Sci 99 Pages: 2349-2355
  • NAID: 10024013752
  • Peer Reviewed
• [Journal Article] High-resolution analysis of chromosome copy number alterations in angioimmunoblastic T-cell lymphoma and peripheral T-cell lymphoma, unspecified, with single nucleotide polymorphism-typing microarrays (2008)
  • Author(s): Fujiwara SI, Yamashita Y, Nakamura N, Choi YL, Ueno T, Watanabe H, Kurashina K, Soda M, Enomoto M, Hatanaka H, Takada S, Abe M, Ozawa K, Mano H.
  • Journal Title: Leukemia 22 Pages: 1891-1898
  • Peer Reviewed
• [Journal Article] Identification of novel isoforms of the EML4-ALK transforming gene in non-small cell lung cancer (2008)
  • Author(s): Choi YL, Takeuchi K, Soda M, Inamura K, Togashi Y, Hatano S, Enomoto M, Hamada T, Haruta H, Watanabe H, Kurashina K, Hatanaka H, Ueno T, Takada S, Yamashita Y, Sugiyama Y, Ishikawa Y, Mano H.
  • Journal Title: Cancer Res 68 Pages: 4971-4976
  • Peer Reviewed
• [Journal Article] Oncogenic mutations of ALK kinase in neuroblastoma (2008)
  • Author(s): Chen Y, Takita J, Choi YL, Kato M, Ohira M, Sanada M, Wang L, Soda M, Kikuchi A, Igarashi T, Nakagawara A, Hayashi Y, Mano H, Ogawa S.
  • Journal Title: Nature 455 Pages: 971-974
  • Peer Reviewed
• [Journal Article] MicroRNA expression profiles of human leukemias (2008)
  • Author(s): Takada S, et.al.
  • Journal Title: Leukemia 22 Pages: 1274-1278
  • Peer Reviewed
• [Journal Article] Functional analysis of JAK3 mutations in transient myeloproliferative disorder and acute megakaryoblastic leukaemia accompanying Down syndrome (2008)
  • Author(s): Sato T, et.al.
  • Journal Title: Br J Haematol 141 Pages: 681-688
  • Peer Reviewed
• [Journal Article] High-resolution analysis of chromosome copy number alterations in angioimmunoblastic T-cell lymphoma and peripheral T-cell lymphoma, unspecified, with single nucleotide polymorphism-typing microarrays (2008)
  • Author(s): Fujiwara S-i, et.al.
  • Journal Title: Leukemia 22 Pages: 1891-1898
  • Peer Reviewed
• [Journal Article] Analysis of chromosome copy number in leukemic cells by different microarray platforms (2007)
  • Author(s): Yamashita Y, Minoura K, Taya T, Fujiwara SI, Kurashina K, Watanabe H, Choi YL, Soda M, Hatanaka H, Enomoto M, Takada S, Mano H.
  • Journal Title: Leukemia 21 Pages: 1333-1337
  • Peer Reviewed
• [Journal Article] Profiling of microRNA expression by mRAP (2007)
  • Author(s): Takada S, Mano H.
  • Journal Title: Nat Protoc 2 Pages: 3136-3145
  • Peer Reviewed
• [Journal Article] Identification of the transforming EML4-ALK fusion gene in non-small-cell lung cancer (2007)
  • Author(s): Soda M, Choi YL, Enomoto M, Takada S, Yamashita Y, Ishikawa S, Fujiwara S, Watanabe H, Kurashina K, Hatanaka H, Bando M, Ohno S, Ishikawa Y, Aburatani H, Niki T, Sohara Y, Sugiyama Y, Mano H.
  • Journal Title: Nature 448 Pages: 561-566
  • Peer Reviewed
• [Journal Article] mRAP, a sensitive method for determination of microRNA expression profiles (2007)
  • Author(s): Mano H, Takada S.
  • Journal Title: Methods 43 Pages: 118-122
  • Peer Reviewed
• [Journal Article] Transforming activity of purinergic receptor P2Y, G-protein coupled, 2 revealed by retroviral expression screening" Biochem (2007)
  • Author(s): Hatanaka H, Takada S, Choi YL, Fujiwara S, Soda M, Enomoto M, Kurashina K, Watanabe H, Yamashita Y, Sugano K, Mano H.
  • Journal Title: Biophys Res Commun 356 Pages: 723-726
  • Peer Reviewed
• [Journal Article] Divergent cytotoxic effects of PKC412 in combination with conventional antileukemic agents in FLT3 mutation-positive versus -negative leukemia cell lines (2007)
  • Author(s): Furukawa Y, Vu HA, Akutsu M, Odgerel T, Izumi T, Tsunoda S, Matsuo Y, Kirito K, Sato Y, Mano H, Kano Y.
  • Journal Title: Leukemia 21 Pages: 1005-1014
  • Peer Reviewed
• [Journal Article] Transforming activity of purinergic receptor P2Y, G protein coupled, 8 revealed by retroviral expression screening (2007)
  • Author(s): Fujiwara S, Yamashita Y, Choi YL, Watanabe H, Kurashina K, Soda M, Enomoto M, Hatanaka H, Takada S, Ozawa K, Mano H.
  • Journal Title: Leuk Lymphoma 48 Pages: 978-986
  • Peer Reviewed
• [Journal Article] A genomic analysis of adult T-cell leukemia (2007)
  • Author(s): Choi YL, Tsukasaki K, O'Neill M C, Yamada Y, Onimaru Y, Matsumoto K, Ohashi J, Yamashita Y, Tsutsumi S, Kaneda R, Takada S, Aburatani H, Kamihira S, Nakamura T, Tomonaga M, Mano H.
  • Journal Title: Oncogene 26 Pages: 1245-1255
  • Peer Reviewed
• [Journal Article] Identification of a constitutively active mutant of JAK3 by retroviral expression screening (2007)
  • Author(s): Choi YL, Kaneda R, Wada T, Fujiwara S, Soda M, Watanabe H, Kurashina K, Hatanaka H, Enomoto M, Takada S, Yamashita Y, Mano H.
  • Journal Title: Leuk Res 31 Pages: 203-209
  • Peer Reviewed
• [Journal Article] Profiling of microRNA expression by mRAP (2007)
  • Author(s): Takada S, Mano H
  • Journal Title: Nature Protocols 2 Pages: 3136-3145
  • Peer Reviewed
• [Journal Article] MicroRNA expression profilies of human leukemias (2007)
  • Author(s): Takada S, Yamashita Y, et. al.
  • Journal Title: Leukemia (In press)
  • Peer Reviewed
• [Journal Article] mRAP, a sensitive method for determination of microRNA expression profiles (2007)
  • Author(s): Mano H, Takada S
  • Journal Title: Methods 43 Pages: 118-122
  • Peer Reviewed
• [Journal Article] A genomic analysis of adult T-cell leukemia. (2007)
  • Author(s): Choi, Y.L.et al.
  • Journal Title: Oncogene 26 Pages: 1245-1255
• [Journal Article] Identification of a constitutively active mutant of JAK3 by retroviral expression screening. (2007)
  • Author(s): Choi, Y.L.et al.
  • Journal Title: Leuk.Res. 31 Pages: 203-209
• [Journal Article] Signals from intra-abdominal fat modulate insulin and leptin sensitivity through different mechanisms: neuronal involvement in food-intake regulation (2006)
  • Author(s): Yamada T, Katagiri H, Ishigaki Y, Ogihara T, Imai J, Uno K, Hasegawa Y, Gao J, Ishihara H, Niijima A, Mano H, Aburatani H, Asano T, Oka Y.
  • Journal Title: Cell Metab 3 Pages: 223-229
  • Peer Reviewed
• [Journal Article] Mouse microRNA profiles determined with a new and sensitive cloning method (2006)
  • Author(s): Takada S, Berezikov E, Yamashita Y, Lagos-Quintana M, Kloosterman WP, Enomoto M, Hatanaka H, Fujiwara S, Watanabe H, Soda M, Choi YL, Plasterk RH, Cuppen E, Mano H.
  • Journal Title: Nucleic Acids Res 34
  • Peer Reviewed
• [Journal Article] Expression of the myeloperoxidase gene in AC133 positive leukemia cells relates to the prognosis of acute myeloid leukemia (2006)
  • Author(s): Taguchi J, Miyazaki Y, Tsutsumi C, Sawayama Y, Ando K, Tsushima H, Fukushima T, Hata T, Yoshida S, Kuriyama K, Honda S, Jinnai I, Mano H, Tomonaga M.
  • Journal Title: Leuk Res 30 Pages: 1105-1112
  • Peer Reviewed
• [Journal Article] DNA microarray analysis of myelodysplastic syndrome (2006)
  • Author(s): Mano H.
  • Journal Title: Leuk Lymphoma 47 Pages: 9-14
  • Peer Reviewed
• [Journal Article] Epigenetic silencing of AXIN2 in colorectal carcinoma with microsatellite instability (2006)
  • Author(s): Koinuma K, Yamashita Y, Liu W, Hatanaka H, Kurashina K, Wada T, Takada S, Kaneda R, Choi YL, Fujiwara SI, Miyakura Y, Nagai H, Mano H.
  • Journal Title: Oncogene 25 Pages: 139-146
  • Peer Reviewed
• [Journal Article] Schedule-dependent interactions between pemetrexed and cisplatin in human carcinoma cell lines in vitro (2006)
  • Author(s): Kano Y, Akutsu M, Tsunoda S, Izumi T, Kobayashi H, Inoue K, Mori K, Fujii H, Mano H, Odgerel T, Furukawa Y.
  • Journal Title: Oncol Res 16 Pages: 85-95
  • Peer Reviewed
• [Journal Article] Many novel mammalian microRNA candidates identified by extensive cloning and RAKE analysis (2006)
  • Author(s): Berezikov E, van Tetering G, Verheul M, van de Belt J, van Laake L, Vos J, Verloop R, van de Wetering M, Guryev V, Takada S, van Zonneveld AJ, Mano H, Plasterk R, Cuppen E.
  • Journal Title: Genome Res 16 Pages: 1289-1298
  • Peer Reviewed
• [Journal Article] DNA microarray analysis of myelodysplastic syndrome (2006)
  • Author(s): Mano H
  • Journal Title: Leuk Lymphoma 47 Pages: 9-14
  • Description: 「研究成果報告書概要(和文)」より
• [Journal Article] Epigenetic silencing of AXIN2 in colorectal carcinoma with microsatellite instability (2006)
  • Author(s): Koinuma K, et al.
  • Journal Title: Oncogene 25 Pages: 139-146
  • Description: 「研究成果報告書概要(和文)」より
• [Journal Article] Gene expression profiles of CD133-positive fractions predict the survival of individuals with acute myeloid leukemia. (2006)
  • Author(s): Yamashita, Y.et al.
  • Journal Title: Cancer Genomics ＆ Proteomics 3 Pages: 169-182
• [Journal Article] Mouse microRNA profiles determined with a new and sensitive cloning method. (2006)
  • Author(s): Takada, S.et al.
  • Journal Title: Nucleic Acids Res. 34
• [Journal Article] Epigenetic silencing of AXIN2 in colorectal carcinoma with microsatellite instability. (2006)
  • Author(s): Koinuma, K.et al.
  • Journal Title: Oncogene 25 Pages: 139-146
• [Journal Article] Screening for genomic fragments that are methylated specifically in colorectal carcinoma with a methylated MLH1 promoter (2005)
  • Author(s): Koinuma K, Kaneda R, Toyota M, Yamashita Y, Takada S, Choi YL, Wada T, Okada M, Konishi F, Nagai H, Mano H.
  • Journal Title: Carcinogenesis 26 Pages: 2078-2085
  • Peer Reviewed
• [Journal Article] Genome-wide screening for target regions of histone deacetylases in cardiomyocytes (2005)
  • Author(s): Kaneda R, Ueno S, Yamashita Y, Choi YL, Koinuma K, Takada S, Wada T, Shimada K, Mano H.
  • Journal Title: Circ Res 97 Pages: 210-218
  • Peer Reviewed
• [Journal Article] Experimental trial for diagnosis of pancreatic ductal carcinoma based on gene expression profiles of pancreatic ductal cells (2005)
  • Author(s): Ishikawa M, Yoshida K, Yamashita Y, Ota J, Takada S, Kisanuki H, Koinuma K, Choi YL, Kaneda R, Iwao T, Tamada K, Sugano K, Mano H.
  • Journal Title: Cancer Sci 96 Pages: 387-393
  • Peer Reviewed
• [Journal Article] Retroviral expression screening of oncogenes in natural killer cell leukemia (2005)
  • Author(s): Choi YL, Moriuchi R, Osawa M, Iwama A, Makishima H, Wada T, Kisanuki H, Kaneda R, Ota J, Koinuma K, Ishikawa M, Takada S, Yamashita Y, Oshimi K, Mano H.
  • Journal Title: Leuk Res 29 Pages: 943-949
  • Peer Reviewed
• [Journal Article] Signal transducers and activators of transcription 3 augments the transcription al activity of CCAAT/enhancer-binding protein alpha in granulocyte colony-stimulating factor signaling pathway (2005)
  • Author(s): Numata A, et al.
  • Journal Title: J Biol Chem 208 Pages: 12621-12629
  • Description: 「研究成果報告書概要(和文)」より
• [Journal Article] Retroviral expression screening of oncogenes in natural killer cell leukemia (2005)
  • Author(s): Choi YL, et al.
  • Journal Title: Leuk Res 29 Pages: 943-949
  • Description: 「研究成果報告書概要(和文)」より
• [Journal Article] Genome-wide screening for target regions of histone deacetylases in cardiomy ocytes (2005)
  • Author(s): Kaneda R, et al.
  • Journal Title: Circ Res 97 Pages: 210-218
  • Description: 「研究成果報告書概要(和文)」より
• [Journal Article] Signal transducers and activators of transcription 3 augments the transcriptional activity of CCAAT/enhancer-binding protein alpha in granulocyte colony-stimulating factor signaling pathway (2005)
  • Author(s): Numata A, et al.
  • Journal Title: J Biol Chem 280 Pages: 12621-12629
  • Description: 「研究成果報告書概要(欧文)」より
• [Journal Article] Genome-wide screening for target regions of histone deacetylases in cardiomyocytes (2005)
  • Author(s): Kaneda R, et al.
  • Journal Title: Circ Res 97 Pages: 210-218
  • Description: 「研究成果報告書概要(欧文)」より
• [Journal Article] Signal transducers and activators of transcription 3 augments the transcriptional activity of CCAAT/enhancer-binding protein alpha in granulocyte colony-stimulating factor signaling pathway (2005)
  • Author(s): Numata A, et al.
  • Journal Title: J Biol Chem 208 Pages: 12621-12629
• [Journal Article] Array-based genomic resequencing of human leukemias
  • Author(s): Yamashita, et al.
  • Journal Title: Oncogene (in press)
  • Peer Reviewed
• [Journal Article] Expression of the myeloperoxidase gene in AC133 positive leukemia cells relates to the prognosis of acute myeloid leukemia
  • Author(s): Taguchi J, et al.
  • Journal Title: Leuk Res (in press)
  • Description: 「研究成果報告書概要(和文)」より
• [Journal Article] Expression of the myeloperoxidase gene in AC133 positive leukemia cells relates to the prognosis of acute myeloid leukemia
  • Author(s): Taguchi J, et al.
  • Journal Title: Leuk Res (in press)
  • Description: 「研究成果報告書概要(欧文)」より
• [Journal Article] Expression of the myeloperoxidase gene in AC133 positive leukemia cells relates to the prognosis of acute myeloid leukemia
  • Author(s): Taguchi J, et al.
  • Journal Title: Leuk Res (in press)
• [Presentation] 高感度miRNAプロファイリング法(mRAP)による癌細胞解析 (2007)
  • Author(s): 高田修治、間野博行
  • Organizer: 日本癌学会学術総会
  • Place of Presentation: 横浜(神奈川県)
  • Year and Date: 2007-10-04