Molecular studies of IG translocation and PVT1 and DCC gene rearrangements in multiple myeloma

2012 Fiscal Year Final Research Report

• Project/Area Number: 22591045
• Research Category: Grant-in-Aid for Scientific Research (C)
• Allocation Type: Single-year Grants
• Section: 一般
• Research Field: Hematology
• Research Institution: Kyoto Prefectural University of Medicine
• Principal Investigator: TANIWAKI Masafumi 京都府立医科大学, 医学研究科, 教授 (80163640)
• Project Period (FY): 2010 – 2012
• Keywords: 多発性骨髄腫 / SKY / FISH / ゲノムアレイ / 遺伝子再構成

Research Abstract

To elucidate pathophysiology of multiple myeloma (MM), we performed molecular dissection of the breakpoints at chromosomal 8q24 and 18q21 rearrangements using FISH, SKY, oligonucleotide array , and RT -PCR procedures. PVT1 rearrangements were detected in 7 (13.0%) of 54 MM patients and 5 (45.5 %) of 11 MM cell lines. Two novel chimeric genes were identified, PVT1-NBEA and PVT1-WWOX. The PVT1-NBEA chimera in which PVT1 exon 1 was fused to NBEA exon 2 and the PVT1-WWOX in which PVT1 exon 1 was fused to WWOX exon 9 were associated with the expression of abnormal NBEA and WWOX lacking their N-terminus, respectively.These findings suggest that PVT1 rearrangements may represent a novel molecular paradigm underlying the pathology of 8q24 rearrangement-positive multiple myeloma. On the other hand, our studies focusing on 18q21 identified abnormal DCC transcripts in which DCC exon 2 was fused to part of DCC intron 1 hence lacking exon 1 in 15 cell lines using bubble PCR for cDNA. Putative abnormal DCC protein lacks a part of N-terminus, suggesting that structural abnormalities of DCC play some roles in the development and progression of MM.

Research Products

• [Journal Article] ADAMTS-13 activity can predict the outcome of disseminated intravascular coagulation in hematologic malignancies treated with recombinant human soluble thrombomodulin (2012)
  • Author(s): Ohshiro M, Kuroda J, Kobayashi Y, Akaogi T, Kawata E, Uoshima N, Kamitsuji Y, Kaneko H, Shimura K, Shimazaki C, Murakami S, Hatsuse M, Okano A, Kobayashi T, Uchiyama H, Matsumoto Y, Horiike S, Taniwaki M
  • Journal Title: Am J Hematol Volume: 87(1) Pages: 116-119
  • Peer Reviewed
• [Journal Article] Double-hit Lymphomas Constitute a Highly Aggressive Subgroup in Diffuse Large B-cell Lymphomas in the Era of Rituximab (2012)
  • Author(s): Kobayashi T, Tsutsumi Y, Sakamoto N, Nagoshi H, Yamamoto-Sugitani M, Shimura Y, Mizutani S, Matsumoto Y, Nishida K, Horiike S, Asano N, Nakamura S, Kuroda J, Taniwaki M
  • Journal Title: Jpn J Clin Oncol Volume: 42(11) Pages: 1035-42
  • Peer Reviewed
• [Journal Article] Overexpression of the DNA sensor proteins, absent in melanoma 2 and interferon-inducible 16, contributes to tumorigenesis of oral squamous cell carcinoma with p53 inactivation (2012)
  • Author(s): Kondo Y, Nagai K, Nakahata S, Saito Y, Ichikawa T, Suekane A, Taki T, Iwakawa R, Enari M, Taniwaki M, Yokota J, Sakoda S, Morishita K
  • Journal Title: Cancer Sci Volume: 103(4) Pages: 782-790
  • Peer Reviewed
• [Journal Article] Establishment of a novel human myeloid leukemia cell line, AMU-AML1, carrying t(12;22)(p13;q11) without chimeric MN1-TEL and with high expression of MN1 (2012)
  • Author(s): Gotou M, Hanamura I, Nagoshi H, Wakabayashi M, Sakamoto N, Tsunekawa N, Horio T, Goto M, Mizuno S, Takahashi M, Suganuma K, Yamamoto H, Hiramatsu A, Watarai M, Shikami M, Imamura A, Mihara H, Taki T, Miwa H, Taniwaki M, Nitta M
  • Journal Title: Genes Chromosomes Cancer Volume: 51(1) Pages: 42-53
  • Peer Reviewed
• [Journal Article] RSK2Ser227 at N-terminal kinase domain is a potential therapeutic target for multiple myeloma (2012)
  • Author(s): Shimura Y, Kuroda J, Ri M, Nagoshi H, Yamamoto-Sugitani M, Kobayashi T, Kiyota M, Nakayama R, Mizutani S, Chinen Y, Sakamoto N, Matsumoto Y, Horiike S, Shiotsu Y, Iida S, Taniwaki M
  • Journal Title: Mol Cancer Ther Volume: 11 Pages: 2600-9
  • Peer Reviewed
• [Journal Article] Retrospective analysis of prognostic factors for angioimmunoblastic T -cell lymphoma: a multicenter cooperative study in Japan (2012)
  • Author(s): Tokunaga T, Shimada K, Yamamoto K, Chihara D, Ichihashi T, Oshima R, Tanimoto M, Iwasaki T, Isoda A, Sakai A, Kobayashi H, Kitamura K, Matsue K, Taniwaki M, Tamashima S, Saburi Y, Masunari T, Naoe T, Nakamura S, Kinoshita T
  • Journal Title: Blood Volume: 119(12) Pages: 2837-2843
  • Peer Reviewed
• [Journal Article] Frequent PVT1 rearrangement and novel chimeric genes PVT1-NBEA and PVT1-WWOX occur in multiple myeloma with 8q24 abnormality (2012)
  • Author(s): Nagoshi H, Taki T, Hanamura I, Nitta M, Otsuki T, Nishida K, Okuda K, Sakamoto N, Kobayashi S, Yamamoto-Sugitani M, Tsutsumi Y, Kobayashi T, Matsumoto Y, Horiike S, Kuroda J, Taniwaki M
  • Journal Title: Cancer Res Volume: 72(19) Pages: 4954-62
  • Peer Reviewed
• [Journal Article] Cytotoxic molecule-positive classical Hodgkin's lymphoma: a clinicopathological comparison with cytotoxic molecule-positive peripheral T -cell lymphoma of not otherwise specified type (2011)
  • Author(s): Asano N, Kinoshita T, Tamaru J, Ohshima K, Yoshino T, Niitsu N, Tsukamoto N, Hirabayashi K, Izutsu K, Taniwaki M, Morishima Y, Nakamura S
  • Journal Title: Haematologica Volume: 11 Pages: 1636-1643
  • Peer Reviewed
• [Journal Article] Eμ/miR-125b transgenic mice develop lethal B-cell malignancies (2011)
  • Author(s): Enomoto Y, Kitaura J, Hatakeyama K, Watanuki J, Akasaka T, Kato N, Shimanuki M, Nishimura K, Takahashi M, Taniwaki M, Haferlach C, Siebert R, Dyer MJS, Asou N, Aburatani H, Nakakuma H, Kitamura T, Sonoki T
  • Journal Title: Eμ/miR-125b transgenic mice develop lethal B-cell malignancies Volume: 25 Pages: 1849-1856
  • Peer Reviewed
• [Journal Article] Identification of IGHCδ-BACH2 fusion transcripts resulting from cryptic chromosomal rearrangements of 14q32 with 6q15 in aggressive B-cell lymphoma/leukemia (2011)
  • Author(s): Kobayashi S, Taki T, Chinen Y, Tsutsumi Y, Ohshiro M, Kobayashi T, Matsumoto Y, Kuroda J, Horiike S, Nishida K, Taniwaki M
  • Journal Title: Genes Chromosomes Cancer Volume: 50 Pages: 207-216
  • Peer Reviewed
• [Journal Article] Bcl-2 is a better therapeutic target than c-Myc, but attacking both could be a more effective treatment strategy for B-cell lymphoma with concurrent Bcl-2 and c-Myc overexpression (2011)
  • Author(s): Sasaki N, Kuroda J, Nagoshi H, Yamamoto M, Kobayashi S, Tsutsumi Y, Kobayashi T, Shimura Y, Matsumoto Y, Taki T, Nishida K, Horiike S, Akao Y, Taniwaki M
  • Journal Title: Exp Hematol Volume: 39(8) Pages: 817-828
  • Peer Reviewed
• [Journal Article] Galectin-3 (Gal-3) induced by leukemia microenvironment promotes drug resistance and bone marrow lodgment in chronic myelogenous leukemia (2011)
  • Author(s): Yamamoto-Sugitani M, Kuroda J, Ashihara E, Nagoshi H, Kobayashi T, Matsumoto Y, Sasaki N, Shimura Y, Kiyota M, Nakayama R, Akaji K, Taki T, Uoshima N, Kobayashi Y, Horiike S, Maekawa T, Taniwaki M
  • Journal Title: Proc Natl Acad Sci U S A Volume: 108(42) Pages: 17468-17473
  • Peer Reviewed
• [Journal Article] Phase II/III study of R-CHOP-21 versus R-CHOP-14 for untreated indolent B-cell non-Hodgkin's lymphoma: JCOG 0203 trial (2011)
  • Author(s): Watanabe T, Tobinai K, Shibata T, Tsukasaki K, Morishima Y, Maseki N, Kinoshita T, Suzuki T, Yamaguchi M, Ando K, Ogura M, Taniwaki M, Uike N, Takeuchi K, Nawano S, Terauchi T, Hotta T
  • Journal Title: J Clin Oncol. Volume: 29 Pages: 3990-3998
  • Peer Reviewed
• [Journal Article] Expression of master regulators of helper T -cell differentiation in peripheral T -cell lymphoma, not otherwise specified, by immunohistochemical analysis (2010)
  • Author(s): Matsumoto Y, Horiike S, Ohshiro M, Yamamoto M, Sasaki N, Tsutsumi Y, Kobayashi T, Shimizu D, Uchiyama H, Kuroda J, Nomura K, Shimazaki C, Taniwaki M
  • Journal Title: Am J Clin Pathol Volume: 133(2) Pages: 281-290
  • Peer Reviewed
• [Journal Article] Cyclin-dependent kinase inhibitor SU9516 enhances sensitivity to methotrexate in human T -cell leukemia Jurkat cells (2010)
  • Author(s): Uchiyama H, Sowa Y, Wakada M, Yogosawa M, Nakanishi R, Horinaka M, Shimazaki C, Taniwaki M, Sakai T
  • Journal Title: Cancer Sci Volume: 101 Pages: 728-734
  • Peer Reviewed
• [Journal Article] Targeting activating transcription factor 3 by Galectin-9 induces apoptosis and overcomes various types of treatment resistance in chronic myelogenous leukemia (2010)
  • Author(s): Kuroda J, Yamamoto M, Nagoshi H, Kobayashi T, Sasaki N, Shimura Y, Horiike S, Kimura S, Yamauchi A, Hirashima M, Taniwaki M
  • Journal Title: Mol Cancer Res Volume: 8 Pages: 994-1001
  • Peer Reviewed
• [Journal Article] Galectin-9 exhibits anti-myeloma activity through JNK and p38 MAP kinase pathways (2010)
  • Author(s): Kobayashi T, Kuroda J, Ashihara E, Oomizu S, Terui Y, Taniyama A, Adachi S, Takagi T, Yamamoto M, Sasaki N, Horiike S, Hatake K, Yamauchi A, Hirashima M, Taniwaki M
  • Journal Title: Leukemia Volume: 24 Pages: 843-850
  • Peer Reviewed
• [Presentation] RSK2Ser227is a therapeutic target of myeloma cells regardless of upstream signalings (2012)
  • Author(s): Shimura Y, Kuroda J, Nagoshi H, M Yamamoto-Sugitani M, Kobayashi T, Kiyota M, Nakayama R, Mizutani S, Chinen Y, Sakamoto N, Matsumoto Y, Horiike S, Ri M, Shiotsu Y, Iida S, Taki T, Taniwaki M
  • Organizer: 54th The American Society of Hematology Annual Meeting and Exposition
  • Place of Presentation: Atlanta. USA
  • Year and Date: 2012-12-09
• [Presentation] Identification of the novel chimeric gene, PVT1-WWOX, in multiple myeloma with 8q24 abnormality (2012)
  • Author(s): Nagoshi H, Taki T, Nishida K, Kuroda J, Chinen Y, Kobayashi S*, Yokokawa Y, Yamamoto-Sugitani M, Kobayashi T, Matsumoto Y, Horiike S, Taniwaki M
  • Organizer: 54th The American Society of Hematology Annual Meeting and Exposition
  • Place of Presentation: Atlanta. USA
  • Year and Date: 2012-12-08
• [Presentation] Frequent rearrangements of PVT1 and a novel PVT1-NBEA chimeric gene in multiple myeloma (2011)
  • Author(s): Nagoshi H, Taki T, Hanamura I, Nishida K, Kuroda J, Okuda K, Kobayashi S, Yamamoto M, Tsutsumi Y, Kobayashi T, Matsumoto Y, Horiike S, Ootsuki T, Nitta M, Taniwaki M
  • Organizer: 第73回日本血液学会学術集会
  • Place of Presentation: 名古屋
  • Year and Date: 20110000
• [Presentation] 8q24 異常を伴う MM における PVT1の関与および新規キメラ遺伝子PVT1-NBEA の同定 (2011)
  • Author(s): 名越久朗,滝 智彦,花村一朗,仁田正和,大槻剛己,西田一弘,奥田恵子,小林 覚,山本未央,〓 康彦,古林 勉,松本洋典,堀池重夫,黒田純也,谷脇雅史
  • Organizer: 第70回日本癌学術総会
  • Place of Presentation: 名古屋
  • Year and Date: 20110000
• [Presentation] Frequent Involvement of PVT1 in Multiple Myeloma Carrying 8q24 Rearrangement and Identification of Novel PVT1-NBEAChimeric Gene (2011)
  • Author(s): Nagoshi H, Taki T, Hanamura I, Nitta M, Otsuki T, Nishida K, Okuda K, Sakamoto N, Kobayashi S, Yamamoto M, Tsutsumi Y, Kobayashi T, Matsumoto Y, Horiike S, Kuroda J, Taniwaki M
  • Organizer: 53th ASH Annual Meeting
  • Place of Presentation: San Diego. USA
  • Year and Date: 2011-12-12
• [Presentation] Leukemia Microenvironment-Specific Galectin-3 Expression of Leukemic Cells Promotes Malignant Niche Formation and Bone Marrow Lodgment of leukemic Cells in Chronic Myelogenous Leukemia (2011)
  • Author(s): Kuroda J, Yamamoto M, Ashihara E, Nagoshi H, Kobayashi T, Matsumoto Y, Sasaki N, Shimura Y, Kiyota M, Nakayama R, Horiike S, Maekawa T, Taniwaki M
  • Organizer: 53th ASH Annual Meeting
  • Place of Presentation: San Diego. USA
  • Year and Date: 2011-12-10
• [Presentation] Expression of altered DCC gene in multiple myeloma and non-Hogdgikin's lymphoma (2010)
  • Author(s): Nagoshi H, Taki T, Kuroda J, Nishida K, Gotoh M, Okuda K, Kobayashi S, Yamamoto M, Tsutsumi Y, Kobayashi T, Matsumoto Y, Horiike S, Otsuki T, Taniwaki M
  • Organizer: 第72回日本血液学会学術集会
  • Place of Presentation: 横浜
  • Year and Date: 20100000
• [Presentation] Identification and Functional Significance of Novel Type of Structurally Aberrant Transcripts of DCC in B-Cell Malignancies (2010)
  • Author(s): Nagoshi H, Taki T, Kuroda J, Nishida K, Gotoh M, Okuda K, Kobayashi S, Yamamoto M, Tsutsumi Y, Kobayashi T, Matsumoto Y, Horiike S, Otsuki T, Taniwaki M
  • Organizer: 52th ASH Annual Meeting
  • Place of Presentation: Orlando, USA
  • Year and Date: 2010-12-06