The elucidation of the mechanisms of growth arrest and apoptosis in myeloma cells induced by PU.1 and its utility for myeloma treatment

2013 Fiscal Year Final Research Report

• Project/Area Number: 23591395
• 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, 准教授 (80363539)
• Project Period (FY): 2011 – 2013
• Keywords: 多発性骨髄腫 / PU.1 / 細胞増殖停止 / 細胞死 / 癌抑制遺伝子

Research Abstract

We conditionally expressed PU.1 in classical Hodgkin lymphoma cell lines, L-428 and KM-H2, and identified that PU.1 induced growth arrest and apoptosis in these cells. Lentiviral transduced PU.1 expression also induced apoptosis in primary Hodgkin lymphoma cells from patients. Therefore, we concluded that PU.1 is a potent tumor suppressor in classical Hodgkin lymphoma cells.
We previously conditional expressed PU.1 also induces growth arrest and apoptosis in myeloma cell lines, U266 and KMS12PE. To test whether PU.1 is a tumor suppressor in mature B cells, including plasma cells, in vivo, we generated conditional PU.1 knockout mice in post germinal center B cells and plasma cells. At the age of 18-24 months, some of these mice shows a proliferation plasma cells in spleen and/or bone marrow. Therefore, PU.1 might be a tumor suppressor in plasma cells in vivo. We are still analyzing these mice.

Research Products

• [Journal Article] PU.1 is a potent tumor suppressor in classical Hodgkin lymphoma cells (2013)
  • Author(s): Yuki H, Ueno S, Tatetsu H, Niiro H, Iino T, Endo S, Kawano Y, Komohara Y, Takeya M, Hata H, Okada S, Watanabe T, Akashi K, Mitsuya H and Okuno Y
  • Journal Title: Blood Volume: 121(6) Pages: 962-970
  • Peer Reviewed
• [Journal Article] Hypoxia reduces CD138 expression and induces an immature and stem cell-like transcriptional program in myeloma cells (2013)
  • Author(s): Kawano Y, Kikukawa Y, Fujiwara S, Wada N, Okuno Y, Mitsuya H, Hata H
  • Journal Title: Int J Oncol Volume: 43(6) Pages: 1809-16
  • Peer Reviewed
• [Journal Article] PDK1 inhibition is a novel therapeutic target in multiple myeloma (2013)
  • Author(s): Fujiwara S, Kawano Y, Yuki H, Okuno Y, Nosaka K, Mitsuya H and Hata H
  • Journal Title: Br J Cancer Volume: 108(1) Pages: 170-178
• [Journal Article] PU.1 is a tumor suppressor for B cell malignancies (2012)
  • Author(s): Okuno Y and Yuki H
  • Journal Title: Oncotarget Volume: 3(12) Pages: 1495-1496
• [Journal Article] Three cases of aggressive natural killer cell leukemia with a lethal hemorrhagic complication (2012)
  • Author(s): Okuno Y, Tatetsu H, Nosaka K and Mitsuya H
  • Journal Title: J Clin Exp Hematop Volume: 52(2) Pages: 101-106
  • Peer Reviewed
• [Journal Article] TRAIL produced from multiple myeloma cells is associated with osteolytic markers (2012)
  • Author(s): Kawano Y, Ueno S, Abe M, Kikukawa Y, Yuki H, Iyama K, Okuno Y, Mitsuya H and Hata H
  • Journal Title: Oncology Reports Volume: 27 Pages: 39-44
  • Peer Reviewed
• [Journal Article] Multiple myeloma cells expressing low levels of CD138 have an immature phenotype and reduced sensitivity to lenalidomide (2012)
  • Author(s): Kawano Y, Fujiwara S, Wada N, Izaki M, Yuki H, Okuno Y, Iyama K, Yamasaki H, Sakai A, Mitsuya H and Hata H
  • Journal Title: Int J Oncol Volume: 41(3) Pages: 876-884
  • Peer Reviewed
• [Journal Article] RUNX1 regulates the CD34 gene in haematopoietic stem cells by mediating interactions with a distal regulatory element (2011)
  • Author(s): Levantini E, Lee S, Radomska H, Hetherington C, Alberich-Jorda M, Amabile G, Zhang P, Gonzalez D, Zhang J, Basseres D, Wilson N, Koschmieder S, Huang G, Zhang D, Ebralidze A, Bonifer C, Okuno Y, Gottgens B, Tenen DG
  • Journal Title: EMBO J Volume: 30(19) Pages: 4059-4070
  • Peer Reviewed
• [Presentation] Successful treatment by VRCD therapy of multiple myeloma (MM) patients refractory to RCD or VCD (2013)
  • Author(s): Yutaka Okuno, Eiko Miyagawa, Rie Furuta, Shinya Hirata, Hiroyuki Hata, Hiroaki Mitsuya
  • Organizer: 日本血液学会
  • Place of Presentation: ロイトン札幌
  • Year and Date: 2013-10-11
• [Presentation] Conditional knockout of PU.1 in plasma cells results in monoclonal gammopathy (2013)
  • Author(s): Shinya Endo, Hiromichi Yuki, Yoshihiro Komohara, Shikiko Ueno, Hiro Tatetsu, Motohiro Takeya, Seiji Okada, Koichi Akashi, Daniel G Tenen, Hiroaki Mitsuya, Yutaka Okuno
  • Organizer: 日本血液学会
  • Place of Presentation: ロイトン札幌
  • Year and Date: 2013-10-11
• [Presentation] IRF4 down-regulation may be involved in PU.1-induced growth arrest/apoptosis in myeloma cells (2013)
  • Author(s): Niina Ueno , Shikiko Ueno, Hiro Tatetsu, Hiromichi Yuki , Hiroyuki Hata, Tadafumi Iino, Hiroaki Niiro, Koichi Akashi, Hiroaki Mitsuya, Yutaka Okuno
  • Organizer: 日本血液学会
  • Place of Presentation: ロイトン札幌
  • Year and Date: 2013-10-11
• [Presentation] PU.1 is a potent tumor suppressor in classical Hodgkin lymphoma cells (2012)
  • Author(s): Hiromichi Yuki , Shikiko Ueno, Hiro Tatetsu, Hiroaki Niiro, Hiroyuki Hata, Seiji Okada, Toshiki Watanabe, Koichi Akashi, Hiroaki Mitsuya, Yutaka Okuno
  • Organizer: 日本血液学会
  • Place of Presentation: 京都国際会議場
  • Year and Date: 2012-10-19
• [Presentation] PU.1-induced growth arrest and apoptosis in classical Hodgkin lymphoma cells (2011)
  • Author(s): Hiromichi Yuki , Shikiko Ueno, Hiroaki Niiro, Hiro Tatetsu, Hiroyuki Hata, Toshiki Watanabe, Seiji Okada, Koichi Akashi, Hiroaki Mitsuya, Yutaka Okuno
  • Organizer: アメリカ血液学会
  • Place of Presentation: サンディエゴ
  • Year and Date: 2011-12-05
• [Presentation] PU.1-induced growth arrest and apoptosis in classical Hodgkin lymphoma cell lines (2011)
  • Author(s): Hiromichi Yuki, Shikiko Ueno, Hiro Tatetsu, Hiroaki Niiro, Hiroyuki Hata, Toshiki Watanabe, Koichi Akashi, Hiroaki Mitsuya, Yutaka Okuno
  • Organizer: 日本血液学会
  • Place of Presentation: 名古屋国際会議場
  • Year and Date: 2011-10-15
• [Book] 血液疾患最新の治療2014-2016, 多発性骨髄腫 (2014)
  • Author(s): 奥野豊、畑裕之
  • Total Pages: 373 (204-207)
  • Publisher: 南江堂
• [Book] みのがしてはならない血液疾患病理からみた44症例 (2014)
  • Author(s): 菰原義弘、奥野豊、竹屋元裕
  • Total Pages: 278 (159-164)
  • Publisher: 医学書院
• [Book] 血液症候群(第2版)III (2013)
  • Author(s): 奥野豊
  • Total Pages: 767 (682-685)
  • Publisher: 日本臨床社