Elucidation of a mechanism of organ tropism in malignant lymphoma to develop novel treatment for intractable extranodal involvement

• Project/Area Number: 26860724
• Research Category: Grant-in-Aid for Young Scientists (B)
• Allocation Type: Multi-year Fund
• Research Field: Hematology
• Research Institution: Nagoya University
• Principal Investigator: SHIMADA Kazuyuki 名古屋大学, 医学部附属病院, 講師 (50631503)
• Project Period (FY): 2014-04-01 – 2017-03-31
• Project Status: Completed (Fiscal Year 2016)
• Budget Amount: ¥3,770,000 (Direct Cost: ¥2,900,000、Indirect Cost: ¥870,000); Fiscal Year 2016: ¥1,300,000 (Direct Cost: ¥1,000,000、Indirect Cost: ¥300,000); Fiscal Year 2015: ¥1,170,000 (Direct Cost: ¥900,000、Indirect Cost: ¥270,000); Fiscal Year 2014: ¥1,300,000 (Direct Cost: ¥1,000,000、Indirect Cost: ¥300,000)
• Keywords: 悪性リンパ腫 / 腫瘍微小環境 / 節外臓器浸潤 / 微小環境

Outline of Final Research Achievements

Although clinical outcomes of malignant lymphoma have been improved due to the application of monoclonal antibody therapies, the outcomes of extranodal involvement including central nervous system during the clinical course are still intractable. In this study, we investigated an underlying mechanism of organ specific lymphoma development using patient derived xenograft models. We could uncover that the inhibition of cell migration was potentially associated with a pathogenesis in intravascular large B-cell lymphoma. Moreover we focused on an amplification of chromosome 19q known to be involved in extranodal B-cell lymphoma. We could also uncover SPIB, a member of the Ets family of transcription factors located on chromosome 19q, was novel poor prognostic factor in diffuse large B-cell lymphoma through an anti-apoptotic mechanism.

Research Products

• [Journal Article] YM155 induces apoptosis through proteasome-dependent degradation of MCL-1 in primary effusion lymphoma. (2017)
  • Author(s): Kojima Y, Hayakawa F, Morishita T, Sugimoto K, Minamikawa Y, Iwase M, Yamamoto H, Hirano D, Imoto N, Shimada K, Okada S, Kiyoi H
  • Journal Title: Pharmacol Res. Volume: in press Pages: 242-251
  • DOI: 10.1016/j.phrs.2017.04.006
  • Peer Reviewed / Open Access
• [Journal Article] Emetine elicits apoptosis of intractable B-cell lymphoma cells with MYC rearrangement through inhibition of glycolytic metabolism. (2017)
  • Author(s): Aoki T, Shimada K, Sakamoto A, Sugimoto K, Morishita T, Kojima Y, Shimada S, Kato S, Iriyama C, Kuno S, Harada Y, Tomita A, Hayakawa F, Kiyoi H.
  • Journal Title: Oncotarget. Volume: 8 Issue: 8 Pages: 13085-13098
  • DOI: 10.18632/oncotarget.14393
  • Peer Reviewed / Open Access / Acknowledgement Compliant
• [Journal Article] SPIB is a novel prognostic factor in diffuse large B-cell lymphoma that mediates apoptosis via the PI3K-AKT pathway. (2016)
  • Author(s): 2.Takagi Y, Shimada K*, Shimada S, Sakamoto A, Naoe T, Nakamura S, Hayakawa F, Tomita A, Kiyoi H.
  • Journal Title: Cancer Sci. Volume: 107 Issue: 9 Pages: 1270-1280
  • DOI: 10.1111/cas.13001
  • Peer Reviewed / Open Access / Acknowledgement Compliant
• [Journal Article] Development and analysis of patient derived xenograft mouse models in intravascular large B-cell lymphoma. Leukemia. (2016)
  • Author(s): Shimada K, Shimada S, Sugimoto K, Nakatochi M, Suguro M, Hirakawa A, Hocking TD, Takeuchi I, Tokunaga T, Takagi Y, Sakamoto A, Aoki T, Naoe T, Nakamura S, Hayakawa F, Seto M, Tomita A, Kiyoi H
  • Journal Title: Leukemia Volume: in press Issue: 7 Pages: 1568-1579
  • DOI: 10.1038/leu.2016.67
  • Peer Reviewed
• [Presentation] Emetine Elicits Apoptosis of Intractable B-Cell Lymphoma Cells with MYC Rearrangement through Inhibition of Glycolytic Metabolism (2016)
  • Author(s): Aoki T, Shimada K, Sakamoto A, Sugimoto K, Morishita T, Kojima Y, Shimada S, Kato S, Iriyama C, Kuno S, Harada Y, Nakamura S, Tomita A, Hayakawa F, Kiyoi H.
  • Organizer: The 58th Annual Meeting and Exposition of the American Society of Hematology
  • Place of Presentation: San Diego (USA)
  • Year and Date: 2016-12-03
  • Int'l Joint Research
• [Presentation] 異種移植マウスモデルを用いた血管内大細胞型B細胞リンパ腫の病態解析 (2016)
  • Author(s): 島田和之
  • Organizer: 第54回日本癌治療学会学術集会
  • Place of Presentation: パシフィコ横浜（神奈川県横浜市）
  • Year and Date: 2016-10-20
  • Invited
• [Presentation] Discovering the novel drug targeting tumor-microenvironment for intractable lymphoma (2016)
  • Author(s): Aoki T, Shimada K, Sakamoto A, Morishita T, Harada Y, Iriyama C, Hayakawa F, Tomita A, Kiyoi H.
  • Organizer: 第78回日本血液学会学術集会
  • Place of Presentation: パシフィコ横浜（神奈川県横浜市）
  • Year and Date: 2016-10-13
• [Presentation] 糖代謝の抑制がmyc陽性DLBCL腫瘍のアポトーシスを誘導する (2016)
  • Author(s): 青木智広、島田和之、坂本明彦、森下喬允、早川文彦、冨田章裕、清井仁
  • Organizer: 第75回日本癌学会学術総会
  • Place of Presentation: パシフィコ横浜（神奈川県横浜市）
  • Year and Date: 2016-10-06
• [Presentation] びまん性大細胞型B細胞リンパ腫における中枢神経浸潤予測因子としての骨髄浸潤の意義 (2016)
  • Author(s): 青木智広、島田和之、入山智沙子、原田靖彦、牛島洋子、冨田章裕、清井仁
  • Organizer: 第56回日本リンパ網内系学会総会
  • Place of Presentation: ホテル日航熊本（熊本県熊本市）
  • Year and Date: 2016-09-01
• [Presentation] Lymph node-associated stromal fibroblasts support B-cell lymphoma cells via the PI3K pathway. (2015)
  • Author(s): Sakamoto A, Shimada K, Katayama M, Hayakawa F, Tomita A, Kiyoi H.
  • Organizer: 第77回日本血液学会学術集会
  • Place of Presentation: 石川県立音楽堂（石川県金沢市）
  • Year and Date: 2015-10-16
• [Presentation] SPIB expression is a novel poor prognostic factor in DLBCL. (2015)
  • Author(s): Takagi Y, Shimada K, Shimada S, Hayakawa F, Sakamoto A, Nakamura S, Tomita A, Kiyoi H.
  • Organizer: 第77回日本血液学会学術集会
  • Place of Presentation: 石川県立音楽堂（石川県金沢市）
  • Year and Date: 2015-10-16
• [Presentation] Lymph node-associated stromal fibroblasts as a potential souse of humoral factors to support B-cell lymphoma cells. (2015)
  • Author(s): Sakamoto A, Shimada K, Katayama M, Hayakawa F, Tomita A, Kiyoi H.
  • Organizer: 第74回日本癌学会学術総会
  • Place of Presentation: 名古屋国際会議場（愛知県名古屋市）
  • Year and Date: 2015-10-08
• [Presentation] Lymph node-associated stromal fibroblasts as a potential source of humoral factors to support B-cell lymphoma cells via the phosphatidylinositol 3-kinase pathway. (2015)
  • Author(s): Sakamoto A, Shimada K, Katayama M, Hayakawa F, Tomita A, Kiyoi H.
  • Organizer: 第44回国際実験血液学会
  • Place of Presentation: 国立京都国際会館（京都府京都市）
  • Year and Date: 2015-09-17
  • Int'l Joint Research
• [Presentation] Development and Analysis of Novel Intravascular Large B-Cell Lymphoma NOD/Shi-Scid IL2Rγnull Mouse Xenograft Model (2014)
  • Author(s): Shimada K,Shimada S,Sugimoto K,Hayakawa F,Katayama M,Hirakawa A,Takagi Y, Nakamura S,Seto M,Naoe T,Tomita A,Kiyoi H.
  • Organizer: The 56th Annual Meeting of the American Society of Hematology.
  • Place of Presentation: San Francisco, USA
  • Year and Date: 2014-12-05 – 2014-12-09
• [Presentation] Intravascular large B-cell lymphoma-from bench to bedside (2014)
  • Author(s): Shimada K
  • Organizer: 第76回日本血液学会学術集会
  • Place of Presentation: 大阪国際会議場（大阪府、大阪市）
  • Year and Date: 2014-10-31 – 2014-11-02
  • Invited
• [Presentation] Biological and genetic analyses of intravascular large B-cell lymphoma using xenograft mouse model (2014)
  • Author(s): Shimada K,Shimada S,Sugimoto K,Hayakawa F,Katayama M,Hirakawa A,Nakamura S,Seto M,Naoe T,Tomita A,Kiyoi H.
  • Organizer: 第76回日本血液学会学術集会
  • Place of Presentation: 大阪国際会議場（大阪府、大阪市）
  • Year and Date: 2014-10-31 – 2014-11-02
• [Patent(Industrial Property Rights)] 血液関連疾患患者のリンパ節由来の間質細胞 (2015)
  • Inventor(s): 清井仁、冨田章裕、早川文彦、島田和之、坂本明彦
  • Industrial Property Rights Holder: 名古屋大学
  • Industrial Property Rights Type: 特許
  • Filing Date: 2015-06-30