The functional involvement of PDPK1 in the pathophysiology of multiple myeloma

• Project/Area Number: 26461429
• Research Category: Grant-in-Aid for Scientific Research (C)
• Allocation Type: Multi-year Fund
• Section: 一般
• Research Field: Hematology
• Research Institution: Kyoto Prefectural University of Medicine
• Principal Investigator: KURODA JUNYA 京都府立医科大学, 医学(系)研究科(研究院), 教授 (70433258)
• Project Period (FY): 2014-04-01 – 2017-03-31
• Project Status: Completed (Fiscal Year 2016)
• Budget Amount: ¥4,810,000 (Direct Cost: ¥3,700,000、Indirect Cost: ¥1,110,000); Fiscal Year 2016: ¥1,170,000 (Direct Cost: ¥900,000、Indirect Cost: ¥270,000); Fiscal Year 2015: ¥1,430,000 (Direct Cost: ¥1,100,000、Indirect Cost: ¥330,000); Fiscal Year 2014: ¥2,210,000 (Direct Cost: ¥1,700,000、Indirect Cost: ¥510,000)
• Keywords: 多発性骨髄腫 / PDPK1 / RSK2 / miR-375 / エピジェネティックス / 分子標的 / 造血器悪性腫瘍 / エピジェネティック / 造血器腫瘍

Outline of Final Research Achievements

This research identified that the constitutive activation of PDPK1/RSK2 signaling pathway is universal in multiple myeloma which is highly heterogenous in terms of their molecular abnormalities. We also identified that the activation of PDPK1/RSK2 signaling is present from the disease initiation phase to the end stage disease, indicating its functional involvement of both disease development and disease progression in multiple myeloma. Indeed, PDPK1/RSK2 regulates myeloma cell survival and proliferation. In addition, we discovered that the abnormal repression of miR-375 by epigenetic dysregulation, such as hypermethylation or hypoacetylation, underlies as the causative of PDPK1 over/expression and its auto-activation in myeloma cells. As the abnormal regulation of miR-375/PDPK1/RSK2 axis is the universally observed in myeloma patients of varied disease stages, novel strategies to manipulate miR-375/PDPK1/RSK2 axis is desired to be developed in future.

Research Products

• [Journal Article] Epigenetic repression of miR-375 is the dominant mechanism for constitutive activation of the PDPK1/RPS6KA3 signalling axis in multiple myeloma. (2017)
  • Author(s): Tatekawa S, Chinen Y, Ri M, Narita T, Shimura Y, Matsumura-Kimoto Y, Tsukamoto T, Kobayashi T, Kawata E, Uoshima N, Taki T, Taniwaki M, Handa H, Iida S, Kuroda J.
  • Journal Title: British Journal of Haematology Volume: 印刷中 Issue: 4 Pages: 534-546
  • DOI: 10.1111/bjh.14707
  • Peer Reviewed / Open Access / Acknowledgement Compliant
• [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] Phosphoinositide protein kinase PDPK1 is a crucial cell signaling mediator in multiple myeloma. (2014)
  • Author(s): Chinen Y, Kuroda J, Shimura Y, Nagoshi H, Kiyota M, Yamamoto-Sugitani M, Mizutani S, Sakamoto N, Ri M, Kawata E, Kobayashi T, Matsumoto Y, Horiike S, Iida S, Taniwaki M.
  • Journal Title: Cancer Res Volume: 74 Issue: 24 Pages: 7418-7429
  • DOI: 10.1158/0008-5472.can-14-1420
  • Peer Reviewed / Open Access
• [Presentation] The Abnormal Repression of Mir-375 Expression By Overlapping Epigenetic Dysregulations in Myelomas. (2016)
  • Author(s): Tatekawa S, Chinen Y, Shimura Y, Matsumura-Kimoto Y, Nagoshi H, Kobayashi T, Kawata E, Narita T, Ri M, Handa H, Uoshima N, Iida S, Kuroda J.
  • Organizer: The American Society of Hematology 57th Annual Meeting and Exposition
  • Place of Presentation: SanDiego, USA
  • Year and Date: 2016-12-03
  • Int'l Joint Research
• [Presentation] The epigenetic dysregulation of miR-375 for PDPK1 overexpression/activation in multiple myeloma. (2016)
  • Author(s): Tatekawa S, Chinen Y, Shimura Y, Kimoto-Matsumura Y, Nagoshi H, Kobayashi T, Kawata E, Narita T, Ri M, Handa H, Uoshima N, Iida S, Kuroda J.
  • Organizer: 第78回日本血液学会学術総会
  • Place of Presentation: 横浜、日本
  • Year and Date: 2016-10-13
  • Int'l Joint Research
• [Presentation] 多発性骨髄腫におけるmiR-375のエピジェネティック異常によるPDPK1発現亢進. (2016)
  • Author(s): 立川章太郎、知念良顕、志村勇司、名越久朗、古林 勉、木元弥生、河田英里、成田朋子、李 政樹、半田 寛、魚嶋伸彦、飯田真介、黒田純也.
  • Organizer: 第41回日本骨髄腫学会学術集会
  • Place of Presentation: 徳島、日本
  • Year and Date: 2016-05-28
• [Presentation] The Epigenetic Repression of Mir-375 Is the Dominant Mechanism for the Constitutive Activation of PDPK1/RSK2 Signaling Axis in Multiple Myeloma. (2015)
  • Author(s): Tatekawa S, Kuroda J, Chinen Y, Shimura Y, Nagoshi H, Kobayashi T, Kawata E, Uoshima N, Handa H, Taniwaki M.
  • Organizer: The American Society of Hematology 57th Annual Meeting and Exposition
  • Place of Presentation: 米国
  • Year and Date: 2015-12-05
  • Int'l Joint Research
• [Presentation] The molecular mechanism of PDPK1 overexpression in multiple myeloma. (2015)
  • Author(s): Tatekawa S, Chinen Y, Shimura Y, Nagoshi H, Kobayashi T, Kawata E, Uoshima N, Handa H, Kuroda J, Taniwaki M.
  • Organizer: 第76回日本血液学会学術総会
  • Place of Presentation: 金沢市
  • Year and Date: 2015-10-16
  • Int'l Joint Research
• [Presentation] 多発性骨髄腫におけるPDPK1発現の分子メカニズム. (2015)
  • Author(s): 立川章太郎、知念良顕、志村勇司、名越久朗、古林 勉、河田英里、魚嶋伸彦、半田 寛、黒田純也、谷脇雅史.
  • Organizer: 第40回日本骨髄腫学会学術集会
  • Place of Presentation: 熊本市
  • Year and Date: 2015-05-16
• [Presentation] 多発性骨髄腫におけるPDPK1の機能的・臨床的意義について. (2015)
  • Author(s): 知念良顕、黒田純也、志村勇司、名越久朗、李 政樹、河田英里、古林 勉、堀池重夫、飯田真介、谷脇雅史.
  • Organizer: 第40回日本骨髄腫学会学術集会
  • Place of Presentation: 熊本市
  • Year and Date: 2015-05-16
• [Presentation] 3-Phosphoinositide-Dependent Protein Kinase 1 (PDPK1) Is a Pivotal Cell Signaling Mediator in Multiple Myeloma. (2014)
  • Author(s): Chinen Y, Kuroda J, Shimura Y, Nagoshi H, Kiyota M, Yamamoto-Sugitani M, Mizutani S, Sakamoto N, Ri M, Kawata E, Kobayashi T, Matsumoto Y, Horiike S, Iida S, Taniwaki M.
  • Organizer: The American Society of Hematology 56th Annual Meeting and Exposition
  • Place of Presentation: San Fransisco, USA
  • Year and Date: 2014-12-06 – 2014-12-09
• [Presentation] Phosphoinositide-dependent protein kinase 1 is a crucial cell signaling mediator in multiple myeloma. (2014)
  • Author(s): Chinen Y, Kuroda J, Shimura Y, Nagoshi H, Kiyota M, Sugitani M, Mizutani S, Sakamoto N, Ri M, Kawata E, Kobayashi T, Matsumoto Y, Horiike S, Iida S, Taniwaki M.
  • Organizer: 第76回日本血液学会学術総会
  • Place of Presentation: 大阪
  • Year and Date: 2014-10-31 – 2014-11-02
• [Book] 造血器腫瘍アトラス改訂第５版 (2016)
  • Author(s): 谷脇雅史、横田昇平、黒田純也
  • Total Pages: 862
  • Publisher: 日本医事新報社
• [Remarks] 京都府立医科大学 血液内科学教室
  • URL: http://www.f.kpu-m.ac.jp/k/hematol/