Genomic alteration in hematologic malignancies and their roles for proliferation and differentiation

2005 Fiscal Year Final Research Report Summary

• Project/Area Number: 16390282
• Research Category: Grant-in-Aid for Scientific Research (B)
• Allocation Type: Single-year Grants
• Section: 一般
• Research Field: Hematology
• Research Institution: Aichi Cancer Center
• Principal Investigator: SETO Masao Aichi Cancer Center, Molecular Medicine, Chief, 遺伝子医療研究部, 部長 (80154665)
• Project Period (FY): 2004 – 2005
• Keywords: MALT lymphoma / API2-MALT1 / Mantle cell lymphoma / DLBCL / Array CGH / Genome alteration / Lymphoma / Chromosome translacation

Research Abstract

1.MALT lymphoma related genes for cell differentiation and proliferation :
MALT1, BCL10 (B-cell lymphoma 10), and API2 (apoptosis inhibitor 2)-MALT1 are key molecules in mucosa-associated lymphoid tissue (MALT) lymphomagenesis. We previously reported that MALT1 and API2- MALT1 were localized only in cytoplasm, where we suggested that both molecules were likely to be active. We examined the localization-determining region by generating various mutants and were able to demonstrate that there were nuclear export signal (NES)-containing domains in the MALT1 C-terminal region. The use of leptomycin B, an NES-specific inhibitor, demonstrated that both MALT1 and API2- MALT1 were predominantly retained in the nuclei, indicating that these molecules were shuttling between nucleus and cytoplasm in an NES-dependent manner.
2.Genomic alterations in malignant lymphoma :
Diffuse large B-cell lymphoma (DLBCL) comprises molecularly distinct subgroups such as activated B- cell-like (ABC) and germinal center B-cell-like (GCB) DLBCL. We previously reported that CD5+ and CD5-CD10+DLBCL constitute clinically relevant subgroups. To determine whether these two subgroups are related to ABC and GCB DLBCL, we analyzed the genomic imbalance of 99 cases using array-CGH. 46 of these cases were subsequently subjected to gene expression profiling. A comparison of genome profiles of distinct subgroups of DLBCL demonstrated specific genomic alterations to each subtype. We have also analyzed Mantle cell lymphoma (MCL) with array CGH technology and found MCL specific genomic alterations. In MCL 2q13 homologous deletion was found in addition to recurrent heterozygous losses. The target gene was found to be BIM1, an antagonist of BCL2, suggesting a role for MCL lymphomagenesis.

Research Products

• [Journal Article] Genomewide array-based comparative genomic hybridization analysis of acute promyelocytic leukemia. (2006)
  • Author(s): Karnan, S.
  • Journal Title: Genes Chrom. Cancer 45 Pages: 420-425
  • Description: 「研究成果報告書概要(和文)」より
• [Journal Article] Identification of subtype-specific genomic alterations in aggressive adult T-cell leukemia/lymphoma. (2006)
  • Author(s): Oshiro, A.
  • Journal Title: Blood in press
  • Description: 「研究成果報告書概要(和文)」より
• [Journal Article] Characterization of target genes at 2p 15-16 amplicon in diffuse large B cell lymphoma. (2006)
  • Author(s): Fukuhara, N.
  • Journal Title: Cancer Science in press
  • Description: 「研究成果報告書概要(和文)」より
• [Journal Article] Genomewide array-based comparative genomic hybridization analysis of acute promyelocytic leukemia. (2006)
  • Author(s): Karnan, S., Tsuzuki, S., Kiyoi, H., Tagawa, H., Ueda, R., Seto, M., Naoe, T.
  • Journal Title: Genes Chrom.Cancer 45 Pages: 420-425
  • Description: 「研究成果報告書概要(欧文)」より
• [Journal Article] Identification of subtype-specific genomic alterations in aggressive adult T-cell leukemia/lymphoma. (2006)
  • Author(s): Oshiro, A., Tagawa, H., Ohshima, K., Karube, K., Uike, N., Tashiro, Y., Utsunomiya, A., Masuda, M., Takasu, N., Nakamura, S., Morishima, Y., Seto, M.
  • Journal Title: Blood (in press)
  • Description: 「研究成果報告書概要(欧文)」より
• [Journal Article] Genome-wide array-based CGH for mantle cell lymphoma : Identification of homozygous deletions of the proapoptotic gene BIM. (2005)
  • Author(s): Tagawa, H.
  • Journal Title: Oncogene 24 Pages: 1348-1358
  • Description: 「研究成果報告書概要(和文)」より
• [Journal Article] Differential expression of cytokines, chemokines and their receptors in follicular lymphoma and reactive follicular hyperplasia : Assessment by complementary DNA microarray. (2005)
  • Author(s): Fujii, A.
  • Journal Title: Oncol. Rep. 13 Pages: 819-824
  • Description: 「研究成果報告書概要(和文)」より
• [Journal Article] Comparison of genome profiles for identification of distinct subgroups of diffuse large B-cell lymphoma. (2005)
  • Author(s): Tagawa, H.
  • Journal Title: Blood 106 Pages: 1770-1777
  • Description: 「研究成果報告書概要(和文)」より
• [Journal Article] API2-MALT1 fusion protein induces transcriptional activation of the API2 gene through NF-kappaB binding elements : evidence for a positive feed-back loop pathway resulting in unremitting NF-kappaB activation. (2005)
  • Author(s): Hosokawa, Y.
  • Journal Title: Biochem. Biophys. Res. Commun. 334 Pages: 51-60
  • Description: 「研究成果報告書概要(和文)」より
• [Journal Article] Genome-wide array-based comparative genomic hybridization of Natural killer cell lymphoma/leukemia : Different genomic alteration patterns of aggressive NK-cell leukemia and extranodal NK/T lymphoma, Nasal type. (2005)
  • Author(s): Nakashima, Y.
  • Journal Title: Genes Chrom. Cancer 44 Pages: 247-255
  • Description: 「研究成果報告書概要(和文)」より
• [Journal Article] A microRNA cluster as a target of genomic amplification in malignant lymphoma. (2005)
  • Author(s): Tagawa, H.
  • Journal Title: Leukemia (Correspondence) 19 Pages: 2013-2016
  • Description: 「研究成果報告書概要(和文)」より
• [Journal Article] BMI-1 Is Highly Expressed in MO-Subtype Acute Myeloid Leukemia. (2005)
  • Author(s): Sawa, M.
  • Journal Title: Int. J. Hematol. 82 Pages: 42-47
  • Description: 「研究成果報告書概要(和文)」より
• [Journal Article] MALT1 contains nuclear export signals and regulates cytoplasmic localization of BCL10. (2005)
  • Author(s): Nakagawa. M.
  • Journal Title: Blood 106 Pages: 4210-4216
  • Description: 「研究成果報告書概要(和文)」より
• [Journal Article] Identification of CCND3 and BYSL as Candidate Targets for the 6p21 Amplification in Diffuse Large B-Cell Lymphoma. (2005)
  • Author(s): Kasuai, Y.
  • Journal Title: Clin. Cancer Res. 11 Pages: 8265-8272
  • Description: 「研究成果報告書概要(和文)」より
• [Journal Article] Genome-wide array-based CGH for mantle cell lymphoma : Identification of homozygous deletions of the proapoptotic gene BIM. (2005)
  • Author(s): Tagawa, H., Karnan, S., Suzuki, R., Matsuo, K., Zhang, X., Ota, A., Morishima, Y., Nakamura, S., Seto, M.
  • Journal Title: Oncogene 24 Pages: 1348-1358
  • Description: 「研究成果報告書概要(欧文)」より
• [Journal Article] Differential expression of cytokines, chemokines and their receptors in follicular lymphoma and reactive follicular hyperplasia : Assessment by complementary DNA microarray. (2005)
  • Author(s): Fujii, A., Oshima, K., Hamasaki, M., Utsunomiya, H., Okazaki, M., Kagami, Y., Seto, M., Kikuchi, M.
  • Journal Title: Oncol.Rep. 13 Pages: 819-824
  • Description: 「研究成果報告書概要(欧文)」より
• [Journal Article] Comparison of genome profile for identification of distinct subgroups of diffuse large B-cell lymphoma. (2005)
  • Author(s): Togawa, H., Suguro, M., Tsuzuki, S., Matsuo, K., Karnan, S., Ohshima, K., Okamoto, M., Morishima, Y., Nakamura, S., Seto, M.
  • Journal Title: Blood 106 Pages: 1770-1777
  • Description: 「研究成果報告書概要(欧文)」より
• [Journal Article] API2-MALT1 fusion protein induces transcriptional activation of the API2 gene through NF-kappaB binding elements : evidence for a positive feed-back loop pathway resulting in unremitting NF-kappaB activation. (2005)
  • Author(s): Hosokawa, Y., Suzuki, H., Nakagawa, M., Lee, TH., Seto, M.
  • Journal Title: Biochem.Biophys.Res.Commun. 334 Pages: 51-60
  • Description: 「研究成果報告書概要(欧文)」より
• [Journal Article] Genome-wide array-based comparative genomic hybridization of Natural killer cell lymphoma/leukemia : Different genomic alteration patterns of aggressive NK-cell leukemia and extranodal NK/T lymphoma, Nasal type. (2005)
  • Author(s): Nakashima, Y., Tagawa, H., Suzuki, R., Karnan, S., Karube, K., Ohshima, K., Muta, K., Nawata, H., Morishima, Y., Nakamura, S., Seto, M.
  • Journal Title: Genes Chrom.Cancer 44 Pages: 247-255
  • Description: 「研究成果報告書概要(欧文)」より
• [Journal Article] A microRNA cluster as a target of genomic amplification in malignant lymphoma. (2005)
  • Author(s): Tagawa, H., Seto, M.
  • Journal Title: Leukemia Correspondence 19 Pages: 2013-2016
  • Description: 「研究成果報告書概要(欧文)」より
• [Journal Article] BMI-1 Is Highly Expressed in M0-Subtype Acute Myeloid Leukemia. (2005)
  • Author(s): Sawa, M., Yamamoto, K., Yokozawa, T., Kiyoi, H., Hishida, A., Kajiguchi, T., Seto, M., Kohno, A., Kitamura, K., Itoh, Y., Asou, N., Hamajima, N., Emi, N., Naoe, T.
  • Journal Title: Int.J.Hematol. 82 Pages: 42-47
  • Description: 「研究成果報告書概要(欧文)」より
• [Journal Article] MALT1 contains nuclear export signals and regulates cytoplasmic localization of BCL10. (2005)
  • Author(s): Nakagawa, M., Hosokawa, Y., Yonezumi, M., Izumiyama, K., Suzuki, R., Tsuzuki, S., Asaka, M., Seto, M.
  • Journal Title: Blood 106 Pages: 4210-4216
  • Description: 「研究成果報告書概要(欧文)」より
• [Journal Article] Identification of CCND3 and BYSL as Candidate Targets for the 6p21 Amplification in diffuse Large B-Cell Lymphoma. (2005)
  • Author(s): Kasugai, Y., Tagawa, H., Kameoka, Y., Morishima, Y., Nakamura, S., Seto, M.
  • Journal Title: Clin.Cancer Res. 11 Pages: 8265-8272
  • Description: 「研究成果報告書概要(欧文)」より
• [Journal Article] Analysis of Chromosomal Imbalances in de novo CD5-Positive Diffuse Large B-cell Lymphoma Detected by Comparative Genomic Hybridization. (2004)
  • Author(s): Karnan, S.
  • Journal Title: Genes, Chromosomes Cancer 39 Pages: 77-81
  • Description: 「研究成果報告書概要(和文)」より
• [Journal Article] Lack Of association between DNA base excision repair gene XRCC1 Gln399Arg polymorphism and risk of malignant lymphoma in Japan. (2004)
  • Author(s): Matsuo, K.
  • Journal Title: Cancer Genet. Cytogenet. 149 Pages: 77-80
  • Description: 「研究成果報告書概要(和文)」より
• [Journal Article] MASL1, a candidate oncogene found in amplification at 8p23.1, is translocated in immunoblastic B-cell lymphoma cell line OCI-LY8. (2004)
  • Author(s): Tagawa, H.
  • Journal Title: Oncogene 23 Pages: 2576-2581
  • Description: 「研究成果報告書概要(和文)」より
• [Journal Article] Identification and Characterization of A Novel Gene, C13orf25, as A Target for 13q31-q32 Amplification in Malignant Lymphoma. (2004)
  • Author(s): Ota, A.
  • Journal Title: Cancer Res. 64 Pages: 3084-3095
  • Description: 「研究成果報告書概要(和文)」より
• [Journal Article] Anti-apoptotic function of API2-MALT1 fusion protein involved in t(11;14)(q21;q21) MALT lymphoma. (2004)
  • Author(s): Hosokawa, Y.
  • Journal Title: Cancer Res. 61 Pages: 3452-3457
  • Description: 「研究成果報告書概要(和文)」より
• [Journal Article] Molecular-cytogenetic Characterization of Non-Hodgkin's Lymphoma with Double and Cryptic Translosations of the Immunoglobulin Heavy Chain Gene. (2004)
  • Author(s): Kanda-Akano, Y.
  • Journal Title: Leuk. Lymphoma 45 Pages: 1559-1567
  • Description: 「研究成果報告書概要(和文)」より
• [Journal Article] Comparison between CD5-Positive and CD5-Negative Cases. (2004)
  • Author(s): Tagawa, H.
  • Journal Title: Cancer Res. 64 Pages: 5948-5955
  • Description: 「研究成果報告書概要(和文)」より
• [Journal Article] Modeling first-hit functions of the t(12;21) TEL-AML1 translocation in mice. (2004)
  • Author(s): Tsuzuki. S.
  • Journal Title: Proc. Natl. Acad. Sci. U S A 101 Pages: 8443-8448
  • Description: 「研究成果報告書概要(和文)」より
• [Journal Article] Genetic and epigenetic factors involved in B-cell lymphomagenesis. (2004)
  • Author(s): Seto, M.
  • Journal Title: Cancer Sci. 95 Pages: 704-710
  • Description: 「研究成果報告書概要(和文)」より
• [Journal Article] Contig array CGH at 3p14.2 points to the FRA3B/FHIT common fragile region as the target gene in diffuse large B-cell lymphoma. (2004)
  • Author(s): Kameoka, Y.
  • Journal Title: Oncogene 23 Pages: 9148-9154
  • Description: 「研究成果報告書概要(和文)」より
• [Journal Article] Comparison of genetic aberrations in CD10^+ diffused large B-cell lymphoma and follicular lymphoma by comparative genomic hybridization and tissue-fluorescence in situ hybridization. (2004)
  • Author(s): Zhang, X.
  • Journal Title: Cancer Sci, 95 Pages: 809-814
  • Description: 「研究成果報告書概要(和文)」より
• [Journal Article] Nuclear Factor KB Activation and Antiapoptosis in Mucosa-Associated Lymphoid Tissue Lymphoma. Hematology. (2004)
  • Author(s): Hosokawa, Y.
  • Journal Title: Int. J. Hematol. 80 Pages: 215-223
  • Description: 「研究成果報告書概要(和文)」より
• [Journal Article] Methylenetetrahydrofolate Reductase Gene (MTHFR) Polymorphisms and Reduced Risk of Malignant Lymphoma. (2004)
  • Author(s): Matsuo, K.
  • Journal Title: Am. J. Hematol. 77 Pages: 351-357
  • Description: 「研究成果報告書概要(和文)」より
• [Journal Article] Gastric MALT Lymphomas Are Divided into Three Groups Based on Responsiveness to Helicobacter Pylori Eradication and Detection of API2-MALT1 Fusion. (2004)
  • Author(s): Inagaki, H.
  • Journal Title: Am. J. Surg. Pathol. 28 Pages: 1560-1567
  • Description: 「研究成果報告書概要(和文)」より
• [Journal Article] Highly efficient delivery of p16 antitumor peptide into aggressive leukemia/lymphoma cells using a novel transporter system. (2004)
  • Author(s): Kondo, E.
  • Journal Title: Mo. Cancer Ther. 3 Pages: 1623-1630
  • Description: 「研究成果報告書概要(和文)」より
• [Journal Article] Analysis of Chromosomal Imbalances in de novo CD5-Positive Diffuse Large B-cell Lymphoma Detected by Comparative Genomic Hybridization. (2004)
  • Author(s): Karnan, S., Tagawa, H., Suzuki, R., Suguro, M., Yamaguchi, M., Okamoto, M., Morishima, Y., Nakamura, S., Seto, M.
  • Journal Title: Genes, Chromosomes Cancer 39 Pages: 77-81
  • Description: 「研究成果報告書概要(欧文)」より
• [Journal Article] Lack of association between DNA base excision repair gene XRCC1 Gln399Arg polymorphism and risk of malignant lymphoma in Japan. (2004)
  • Author(s): Mastuo, K., Hamajima, N., Suzuki, R., Andoh, M., Nakamura, S., Seto, M., Morishima, Y, Tajima, K.
  • Journal Title: Cancer Genet.Cytogenet. 149 Pages: 77-80
  • Description: 「研究成果報告書概要(欧文)」より
• [Journal Article] MASL1, a candidate oncogene found in amplification at 8p23.1, is translocated in immunoblastic B-cell lymphoma cell line OCI-LY8. (2004)
  • Author(s): Tagawa, H., Karnan, S., Kasugai, Y., Tuzuki, S., Suzuki, R., Hosokawa, Y., Seto, M.
  • Journal Title: Oncogene 23 Pages: 2576-2581
  • Description: 「研究成果報告書概要(欧文)」より
• [Journal Article] Identification and Characterization of A Novel Gene, C13orf25, as A Target for 13q31-q32 Amplification in Malignant Lymphoma. (2004)
  • Author(s): Ota, A., Tagawa, H., Karnan, S., Suzuki, Y., Karpas, A., Kira, S., Yoshida, Y., Seto, M.
  • Journal Title: Cancer Res. 64 Pages: 3087-3095
  • Description: 「研究成果報告書概要(欧文)」より
• [Journal Article] Anti-apoptotic function of API2-MALT1 fusion protein involved in t(11;18)(q21;q21)MALT lymphoma. (2004)
  • Author(s): Hosokawa, Y., Suzuki, H., Suzuki, Y., Takahashi, R., Seto, M.
  • Journal Title: Cancer Res. 64 Pages: 3452-3457
  • Description: 「研究成果報告書概要(欧文)」より
• [Journal Article] Molecular-cytogenetic Characterization of Non-Hodgkin's Lymphoma with Double and Cryptic Translocations of the Immunoglobulin Heavy Chain Gene. (2004)
  • Author(s): Kanda-Akano, Y., Nomura, K., Fujita, Y., Horiike, S., Nishida, K., Nagai, M., Miura, I., Nakamura, S., Seto, M., Iida, S., Ueda, R., Taniwaki, M.
  • Journal Title: Leuk.Lymphoma 45 Pages: 1559-1567
  • Description: 「研究成果報告書概要(欧文)」より
• [Journal Article] Genome-Wide Array-based Comparative Genomic Hybridization of Diffuse Large B-Cell Lymphoma : Comparison between CD5-Positive and CD5-Negative Cases. (2004)
  • Author(s): Tagawa, H., Tsuzuki, S., Suzuki, R., Karnan, S., Ota, A., Matsuo, K., Yamaguchi, M., Morishima, Y., Nakamura, S., Seto, M.
  • Journal Title: Cancer Res. 64 Pages: 5948-5955
  • Description: 「研究成果報告書概要(欧文)」より
• [Journal Article] Modeling first-hit functions of the t(12;21)TEL-AML1 translocation in mice. (2004)
  • Author(s): Tsuzuki, S., Seto, M., Greaves, M., Enver, T.
  • Journal Title: Proc.Natl.Acad.Sci.USA 101 Pages: 8443-8448
  • Description: 「研究成果報告書概要(欧文)」より
• [Journal Article] Contig array CGH at 3p14.2 points to the FRA3B/FHIT common fragile region as the target gene in diffuse large B-cell lymphoma. (2004)
  • Author(s): Kameoka, Y., Tagawa, H., Tsuzuki, S., Karnan S., Ota, A., Suguro, M., Suzuki, R., Yamaguchi, M., Morishima, Y., Nakamura, S., Seto, M.
  • Journal Title: Oncogene 23 Pages: 9148-9154
  • Description: 「研究成果報告書概要(欧文)」より
• [Journal Article] Comparison of genetic aberrations in CD10^+ diffused large B-cell lymphoma and follicular lymphoma by comparative genomic hybridization and tissue-fluorescence in situ hybridization. (2004)
  • Author(s): Zhang, X., Karnan, S., Tagawa, H., Suzuki, R., Tsuzuki, S., Hosokawa, Y., Morishima, Y., Nakamura, S., Seto, M.
  • Journal Title: Cancer Sci. 95 Pages: 809-814
  • Description: 「研究成果報告書概要(欧文)」より
• [Journal Article] Nuclear Factor KB Activation and Antiapoptosis in Mucosa-Associated Lymphoid Tissue Lymphoma. (2004)
  • Author(s): Hosokawa, Y., Seto, M.
  • Journal Title: Int.J.Hematol. 80 Pages: 215-223
  • Description: 「研究成果報告書概要(欧文)」より
• [Journal Article] Methylenetetrahydrofolate Reductase Gene (NTHFR) Polymorphisms and Reduced Risk of Malignant Lymphoma. (2004)
  • Author(s): Matsuo, K., Hamajima, N., Suzuki, R., Ogura, M., Kagami, Y., Taji, H., Yasue, T., Mueller, NE., Nakamura, S., Seto, M., Morishima, Y., Tajima, K.
  • Journal Title: Am.J.Hematol. 77 Pages: 351-357
  • Description: 「研究成果報告書概要(欧文)」より
• [Journal Article] Gastric MALT Lymphoma Are Divided into Three Groups Based on Responsiveness to Helicobacter Pylori Eradication and Detection of API2-MALT1 Fusion. (2004)
  • Author(s): Inagaki, H., Nakamura, T., Li, C., Sugiyama, T., Asaka, M., Kodaira, J., Iwano, M., Chiba, T., Okazaki, K., Kato, A., Ueda, R., Eimoto, T., Okamoto, S., Sasaki, N., Uemura, N., Akamatsu, T., Miyabayashi, H., Kawamura, Y., Goto, H., Niwa, Y., Yokoi, T., Seto, M., Makamura, S.
  • Journal Title: Am.J.Surg.Pathol. 28 Pages: 1560-1567
  • Description: 「研究成果報告書概要(欧文)」より
• [Journal Article] Highly efficient delivery of p16 antitumor peptide into aggressive leukemia/lymphoma cells using a novel transporter system. (2004)
  • Author(s): Kondo, E., Seto, M., Yoshikawa, K., Yoshino, T.
  • Journal Title: Mol.Cancer Ther. 3 Pages: 1623-1630
  • Description: 「研究成果報告書概要(欧文)」より
• [Patent(Industrial Property Rights)] Method for prognosis B-cell lymphoma (2005)
  • Inventor(s): 瀬戸加大 他3名
  • Industrial Property Rights Holder: 愛知県,日本ガイシ
  • Industrial Property Number: 国際特許分類:なし(PCT出願)
  • Filing Date: 2005-04-19
  • Description: 「研究成果報告書概要(和文)」より
• [Patent(Industrial Property Rights)] 悪性リンパ腫の診断及び予後診断の方法 (2005)
  • Inventor(s): 瀬戸加大 他3名
  • Industrial Property Rights Holder: 愛知県,日本ガイシ
  • Industrial Property Number: 国際特許分類:C12N 15/09
  • Filing Date: 2005-12-05
  • Description: 「研究成果報告書概要(和文)」より
• [Patent(Industrial Property Rights)] 遺伝子検出方法、及びDNAマイクロアレイ (2005)
  • Inventor(s): 瀬戸加大 他3名
  • Industrial Property Rights Holder: 愛知県,日本ガイシ
  • Industrial Property Number: 国際特許分類:C12N 15/09
  • Filing Date: 2005-09-12
  • Description: 「研究成果報告書概要(和文)」より