Treatment strategy with PU.1 induction in multiple myeloma and Hodgkin lymphoma

• Project/Area Number: 26461427
• Research Category: Grant-in-Aid for Scientific Research (C)
• Allocation Type: Multi-year Fund
• Section: 一般
• Research Field: Hematology
• Research Institution: Kumamoto University
• Principal Investigator: Okuno Yutaka 熊本大学, 大学院生命科学研究部(医), 准教授 (80363539)
• Project Period (FY): 2014-04-01 – 2018-03-31
• Project Status: Completed (Fiscal Year 2017)
• Budget Amount: ¥4,940,000 (Direct Cost: ¥3,800,000、Indirect Cost: ¥1,140,000); Fiscal Year 2016: ¥1,560,000 (Direct Cost: ¥1,200,000、Indirect Cost: ¥360,000); Fiscal Year 2015: ¥1,690,000 (Direct Cost: ¥1,300,000、Indirect Cost: ¥390,000); Fiscal Year 2014: ¥1,690,000 (Direct Cost: ¥1,300,000、Indirect Cost: ¥390,000)
• Keywords: PU.1 / tumor suppressor / 悪性リンパ腫 / 多発性骨髄腫 / IRF4 / IRF7 / IFNβ / 細胞死 / DLBCL / びまん性大細胞型B細胞リンパ腫 / 腫瘍抑制因子 / IFNb / ホジキンリンパ腫 / apoptosis / cell cycle arrest / 化合物スクリーニング / 分子標的療法薬 / 新規薬剤

Outline of Final Research Achievements

We generated conditional knockout of PU.1 by crossing Cγ1-Cre and PU.1-loxP mice. 75% of the aged knockout mice emerged diffuse large B cell lymphoma, indicating that PU.1 acts as tumor suppressor in B cells.
PU.1 expression induces cell cycle arrest and apoptosis in myeloma cells. We uncovered that PU.1 binds to IRF4 promoter and suppresses IRF4 expression. It was previously reported that IRF4 suppresses IRF7 expression by direct binding to its promoter. Indeed, we found that decreased IRF4 expression subsequently induces IRF7 expression that induces IFNβ expression. IFNβ is expressed in myeloma cells after PU.1 expression and knockdown of IFNβ partially prevent myeloma cells from apoptosis. In conclusion, PU.1 induces apoptosis in myeloma cells by suppression of IRF4 expression and subsequent up-regulation of IRF7 and IFNβ.

Research Products

• [Journal Article] PU.1 acts as tumor suppressor for myeloma cells through direct transcriptional repression of IRF4 (2017)
  • Author(s): Ueno N, Nishimura N, Ueno S, Endo S, Tatetsu H, Hirata S, Hata H, Matsuoka M, Mitsuya H, Okuno Y.
  • Journal Title: Oncogene Volume: 36 Issue: 31 Pages: 4481-4497
  • DOI: 10.1038/onc.2017.79
  • Peer Reviewed
• [Journal Article] Restoring PU.1 induces apoptosis and modulates viral transactivation via interferon-stimulated genes in primary effusion lymphoma (2017)
  • Author(s): Goto H、Kariya R、Kudo E、Okuno Y、Ueda K、Katano H、Okada S
  • Journal Title: Oncogene Volume: 36 Issue: 37 Pages: 5252-5262
  • DOI: 10.1038/onc.2017.138
  • Peer Reviewed
• [Journal Article] Cell adhesion molecule-1 (CADM1) expressed on adult T-cell leukemia/lymphoma cells is not involved in the interaction with macrophages. (2017)
  • Author(s): Komohara Y, Ma C, Yano H, Pan C, Horlad H, Saito Y, Ohnishi K, Fujiwara Y, Okuno Y, Nosaka K, Shimosaki S, Morishita K, Matsuoka M, Wakayama T, Takeya M
  • Journal Title: Journal of Clinical and Experimental Hematopathology Volume: 57 Issue: 1 Pages: 15-20
  • DOI: 10.3960/jslrt.17003
  • NAID: 130005709559
  • ISSN: 1346-4280, 1880-9952
  • Peer Reviewed / Open Access
• [Journal Article] A xenograft model reveals that PU.1 functions as a tumor suppressor for multiple myeloma in vivo. (2017)
  • Author(s): Nishimura N, Endo S, Ueno S, Ueno N, Tatetsu H, Hirata S, Hata H, Komohara Y, Takeya M, Mitsuya H, Okuno Y.
  • Journal Title: Biochem Biophys Res Commun. Volume: 486 Issue: 4 Pages: 916-922
  • DOI: 10.1016/j.bbrc.2017.03.124
• [Journal Article] A xenograft model reveals that PU.1 functions as a tumor suppressor for multiple myeloma in vivo (2017)
  • Author(s): Nishimura N, Endo S, Ueno S, Ueno N, Tatetsu H, Hirata S, Hata H, Komohara Y, Takeya M, Mitsuya H, Okuno Y.
  • Journal Title: Biochem Biophys Res Commun. Volume: In press
  • Peer Reviewed
• [Journal Article] Immunomodulatory drugs act as inhibitors of DNA methyltransferases and induce PU.1 up-regulation in myeloma cells. (2015)
  • Author(s): Endo S, Amano M, Nishimura N, Ueno N, Ueno S, Yuki H, Fujiwara S, Wada N, Hirata S, Hata H, Mitsuya H, Okuno Y.
  • Journal Title: Biochem Biophys Res Commun. Volume: 469 Issue: 2 Pages: 236-242
  • DOI: 10.1016/j.bbrc.2015.11.116
  • Peer Reviewed
• [Journal Article] Transcriptional dysregulation of the deleted in colorectal carcinoma gene in multiple myeloma and monoclonal gammopathy of undetermined significance. (2015)
  • Author(s): Nagoshi H, Taki T, Chinen Y, Tatekawa S, Tsukamoto T, Maegawa S, Yamamoto-Sugitani M, Tsutsumi Y, Kobayashi T, Matsumoto Y, Horiike S, Okuno Y, Fujiwara S, Hata H, Kuroda J, Taniwaki M.
  • Journal Title: Genes Chromosomes Cancer Volume: 54 Issue: 12 Pages: 788-795
  • DOI: 10.1002/gcc.22290
  • Peer Reviewed / Open Access / Int'l Joint Research
• [Journal Article] Lactate, a putative survival factor for myeloma cells, is incorporated by myeloma cells through monocarboxylate transporters 1 (2015)
  • Author(s): Fujiwara S, Wada N, Kawano Y, Okuno Y, Kikukawa Y, Endo S, Nishimura N, Ueno N, Mitsuya H, Hata H.
  • Journal Title: Exp Hematol Oncol. Volume: 21 Issue: 1
  • DOI: 10.1186/s40164-015-0008-z
  • Peer Reviewed / Open Access / Acknowledgement Compliant
• [Journal Article] Shikonin, dually functions as a proteasome inhibitor and a necroptosis inducer in multiple myeloma cells. (2015)
  • Author(s): Wada N, Kawano Y, Fujiwara S, Kikukawa Y, Okuno Y, Tasaki M, Ueda M, Ando Y, Yoshinaga K, Ri M, Iida S, Nakashima T, Shiotsu Y, Mitsuya H, Hata H.
  • Journal Title: International Journal of Oncology Volume: 46 Issue: 3 Pages: 963-972
  • DOI: 10.3892/ijo.2014.2804
  • Peer Reviewed / Open Access / Acknowledgement Compliant
• [Journal Article] Complete remission achieved by a combination regimen with bortezomib, cyclophosphamide, and dexamethasone in a multiple myeloma patient with elevated serum KL-6 level. (2014)
  • Author(s): Okuno Y, Nishimura N, Nosaka K, Hata H, Mitsuya H.
  • Journal Title: 臨床血液 Volume: 55 Pages: 948-952
  • NAID: 130004920674
  • Peer Reviewed
• [Journal Article] Regression of primary rectal MALT lymphoma after Helicobacter pylori eradication. (2014)
  • Author(s): Nosaka K, Shono T, Yonemura Y, Iyama K, Sasaki Y, Endo S, Okuno Y, Mitsuya H.
  • Journal Title: 臨床血液 Volume: 55 Pages: 948-952
  • NAID: 130004688008
  • Peer Reviewed
• [Journal Article] Combined use of bortezomib, cyclophosphamide, and dexamethasone induces favorable hematological and organ responses in Japanese patients with amyloid light-chain amyloidosis: a single-institution retrospective study. (2014)
  • Author(s): Kikukawa Y, Yuki H, Hirata S, Ide K, Nakata H, Miyakawa T, Matsuno N, Nosaka K, Yonemura Y, Kawaguchi T, Hata H, Mitsuya H, Okuno Y.
  • Journal Title: International Journal of Hematology Volume: 101 Issue: 2 Pages: 133-139
  • DOI: 10.1007/s12185-014-1705-9
  • Peer Reviewed / Acknowledgement Compliant
• [Presentation] PU.1 down-regulates IRF4 by direct transcriptional suppression in myeloma cells (2017)
  • Author(s): Niina Ueno, Nao Nishimura, Shikiko Ueno, Shinya Endo, Hiro Tatetsu, Masao Matsuoka, Hiroaki Mitsuya, and Yutaka Okuno
  • Organizer: 日本血液学会
• [Presentation] A case of multiple myeloma suffered from interstitial pneumonitis induced by carfilzomib treatment (2017)
  • Author(s): Miyu Sonoda, Hiro Tatetsu, Shikiko Ueno, Yawara Kawano, Kisato Nosaka, Masao Matsuoka, Yutaka Okuno
  • Organizer: 日本血液学会
• [Presentation] PU.1-Induced IRF4 Down-Regulation and Subsequent IRF7 up-Regulation in Myeloma Cells (2016)
  • Author(s): Niina Ueno, Shikiko Ueno, Shinya Endo, Nao Nishimura, Hiro Tatetsu, Shinya Hirata, Hiroaki Mitsuya, and Yutaka Okuno
  • Organizer: アメリカ血液学会
  • Place of Presentation: Orange County Convention Center, Orland, USA
  • Year and Date: 2016-12-06
  • Int'l Joint Research
• [Presentation] PU.1-induced IRF4 down-regulation and subsequent IRF7 up-regulation in myeloma cells (2016)
  • Author(s): Niina Ueno, Shikiko Ueno, Shinya Endo, Nao Nishimura, Hiro Tatetsu, Kisato Nosaka, Shinya Hirata, Hiroaki Mitsuya, and Yutaka Okuno
  • Organizer: 日本血液学会
  • Place of Presentation: ホテル金沢
  • Year and Date: 2016-10-18
• [Presentation] IMiDs up-regulate PU.1 expression in myeloma cell through demethylation of the PU.1 promoter region (2016)
  • Author(s): Shinya Endo, Masayuki Amano, Nao Nishimura, Shikiko Ueno, Niina Ueno, Hiromichi Yuki, ShihoFujiwara, Naoko Wada, Shinya Hirata, Hiroyuki Hata, Hiroaki Mitsuya, and Yutaka Okuno
  • Organizer: 日本血液学会
  • Place of Presentation: ホテル金沢
  • Year and Date: 2016-10-18
• [Presentation] OSSL_325096 Induces Apoptosis in Multiple Myeloma Cells through VCP inhibition (2016)
  • Author(s): Nao Nishimura, Eri Fuji, Shinya Endo, Niina Ueno, Hironori Hayashi, Masayuki Amano, Hiroyuki Hata, Hiroaki Mitsuya, and Yutaka Okuno
  • Organizer: 日本血液学会
  • Place of Presentation: 石川県立音楽堂 地下1階 交流ホール
  • Year and Date: 2016-10-16
• [Presentation] Preference usage of certain V regions in AL amyloidosis patients (2016)
  • Author(s): Nao Nishimura, Shinya Endo, Eri Fuji, Niina Ueno, Shikiko Ueno, Hiromichi Yuki, Hiroyuki Hata, Yutaka Okuno
  • Organizer: 日本血液学会
  • Place of Presentation: パシフィコ横浜
  • Year and Date: 2016-10-13
• [Presentation] Serum KL-6 elevation is associated with aggressive phenotype of multiple myeloma (2016)
  • Author(s): Shinya Endo, Nao Nishimura, Shikiko Ueno, Yutaka Okuno
  • Organizer: 日本血液学会
  • Place of Presentation: パシフィコ横浜
  • Year and Date: 2016-10-13
• [Presentation] ALアミロイドーシス患者における免疫グロブリン軽鎖遺伝子可変領域選択性 (2016)
  • Author(s): Nao Nishimura, Shinya Endo, Eri Fuji, Niina Ueno, Shikiko Ueno, Hiromichi Yuki, Hiroyuki Hata, Yutaka Okuno
  • Organizer: 日本骨髄腫学会
  • Place of Presentation: あわぎんホール
  • Year and Date: 2016-05-28
• [Presentation] PU.1 is tumor suppressor for B cell Malignancies (2016)
  • Author(s): 奥野 豊
  • Organizer: リンパ網内系学会
  • Place of Presentation: ホテル日航熊本
  • Invited
• [Presentation] Conditional knockout of Sfpi1 in post germinal center B and plasma cells induces B cell lymphoma and plasma cell neoplasm (2014)
  • Author(s): 遠藤慎也
  • Organizer: アメリカ血液学会
  • Place of Presentation: San Francisco Moscone Center
  • Year and Date: 2014-12-06
• [Presentation] Xenograft models of multiple myeloma reveal that PU.1 serves as a tumor suppressor for multiple myeloma (2014)
  • Author(s): 西村直
  • Organizer: アメリカ血液学会
  • Place of Presentation: San Francisco Moscone Center
  • Year and Date: 2014-12-06
• [Presentation] Deletion of Sfpi1 in the lineages from post GC B cells to plasma cells induces B cell malignancies (2014)
  • Author(s): 遠藤慎也
  • Organizer: 日本血液学会
  • Place of Presentation: 大阪国際会議場
  • Year and Date: 2014-11-02
• [Presentation] PU.1 is a tumor suppressor in multiple myeloma cells in xenograft models (2014)
  • Author(s): 西村直
  • Organizer: 日本血液学会
  • Place of Presentation: 大阪国際会議場
  • Year and Date: 2014-10-31