Analyzing the mechanism of TKI-resistance in Ph-positive ALL

• Project/Area Number: 25461404
• Research Category: Grant-in-Aid for Scientific Research (C)
• Allocation Type: Multi-year Fund
• Section: 一般
• Research Field: Hematology
• Research Institution: Hokkaido University
• Principal Investigator: KONDO TAKESHI 北海道大学, 医学(系)研究科(研究院), 講師 (70333606)
• Co-Investigator(Kenkyū-buntansha): OHBA Yusuke 北海道大学, 大学院医学研究科, 教授 (30333503)
• Co-Investigator(Renkei-kenkyūsha): MINAMI YOSUKE 神戸大学, 医学部附属病院, 講師 (60513752)
• Project Period (FY): 2013-04-01 – 2016-03-31
• Project Status: Completed (Fiscal Year 2015)
• Budget Amount: ¥5,070,000 (Direct Cost: ¥3,900,000、Indirect Cost: ¥1,170,000); Fiscal Year 2015: ¥2,210,000 (Direct Cost: ¥1,700,000、Indirect Cost: ¥510,000); Fiscal Year 2014: ¥1,300,000 (Direct Cost: ¥1,000,000、Indirect Cost: ¥300,000); Fiscal Year 2013: ¥1,560,000 (Direct Cost: ¥1,200,000、Indirect Cost: ¥360,000)
• Keywords: BCR-ABL / TKI / Ph+ALL / チロシンキナーゼ阻害剤 / SUMO化 / leukemia / Leukemia / Drug Resistance

Outline of Final Research Achievements

Using the FRET-based drug sensitivity test, we identified and isolated TKI-rafractory cell population in Ph-positive ALL. Analysis of gene expression profile in TKI-refractory cells indicated that so many intracellular pathways were activated. One of them was sumoylation pathway. In vitro analysis, we proved that BCR-ABL is sumoylated. Moreover, inhibition of sumoylation effectively induced apoptosis in Ph+ALL cells.

Research Products

• [Journal Article] Pharmacokinetics and pharmacodynamics of dasatinib in the chronic phase of newly diagnosed chronic myeloid leukemia. (2016)
  • Author(s): Ishida Y, Murai K, Yamaguchi K, Miyagishima T, Shindo M, Ogawa K, Nagashima T, Sato S, Watanabe R, Yamamoto S, Hirose T, Saitou S, Yonezumi M, Kondo T, Kato Y, Mochizuki N, Ohno K, Kishino S, Kubo K, Oyake T, Ito S; Inter-Michinoku Dasatinib Study Group (IMIDAS)
  • Journal Title: Eur J Clin Pharmacol. Volume: 72 Issue: 2 Pages: 185-193
  • DOI: 10.1007/s00228-015-1968-y
  • Peer Reviewed
• [Journal Article] Upregulation of microRNA-126-5p is associated with drug resistance to cytarabine and poor prognosis in AML patients. (2015)
  • Author(s): Shibayama Y, Kondo T, Ohya H, Fujisawa S, Teshima T, Iseki K.
  • Journal Title: Oncol Rep. Volume: 33 Issue: 5 Pages: 2176-2182
  • DOI: 10.3892/or.2015.3839
  • Peer Reviewed / Open Access
• [Journal Article] Ultra-high level of serum soluble interleukin-2 receptor at diagnosis predicts poor outcome for angioimmunoblastic T-cell lymphoma. (2015)
  • Author(s): Shiratori S, Kosugi-Kanaya M, Shigematsu A, Kobayashi H, Yamamoto S, Kobayashi N, Iwasaki H, Mori A, Kunieda Y, Yutaka T, Kurosawa M, Kakinoki Y, Endo T, Kondo T, Hashino S, Teshima T
  • Journal Title: Leukemia & Lymphoma Volume: - Issue: 9 Pages: 2592-2597
  • DOI: 10.3109/10428194.2014.1001985
  • Peer Reviewed / Acknowledgement Compliant
• [Journal Article] FIP1L1 presence in FIP1L1-RARA or FIP1L1-PDGFRA differentially contributes to the pathogenesis of distinct types of leukemia (2014)
  • Author(s): Junko Iwasaki, Takeshi Kondo, Stephanie Darmanin, Makoto Ibata, Masahiro Onozawa, Daigo Hashimoto, Naoya Sakamoto and Takanori Teshima
  • Journal Title: Annals of Hematology Volume: 未定 Issue: 9 Pages: 1473-1482
  • DOI: 10.1007/s00277-014-2085-1
  • NAID: 120005656326
  • Peer Reviewed
• [Presentation] 成人CMLにおける移植前チロシンキナーゼ阻害剤使用と移植成績の解析～TKI時代での検討 (2016)
  • Author(s): 近藤 健、大橋一輝、長村登紀子、東條有伸、内田直之、中前博久、矢野真吾、福田隆浩、橋本尚子、鬼塚真仁、高梨美乃子、一戸辰夫、熱田由子、豊嶋崇徳
  • Organizer: 第３８回日本造血細胞移植学会総会
  • Place of Presentation: 名古屋国際会議場（愛知県・名古屋市）
  • Year and Date: 2016-03-03
• [Presentation] IDENTIFICATION OF FIP1L1-PDGFRA ASSOCIATING MOLECULE THAT LOCATES IN THE NUCLEUS AND AUGMENTS THE ACTIVITY OF FIPAL1-PDGFRA. (2015)
  • Author(s): Takeshi Kondo, Makoto Ibata, Junko Iwasaki, Yoichiro Fujioka, Koji Nakagawa, Stephanie Darmanin, Masahiro Onozawa, Daigo Hashimoto, Yusuke Ohba, Shigetsugu Hatakeyama, Takanori Teshima
  • Organizer: European Association of Hematology 20th Congress
  • Place of Presentation: Vienna (Austria)
  • Year and Date: 2015-06-11
  • Int'l Joint Research
• [Presentation] FRET-based drug sensitivity test predicts clinical response of nilotinib in CML-CP patients. (2014)
  • Author(s): Kondo T, Ohba Y, Fujisawa S, Miyagishima T, Mori A, Iwasaki H, Shindo M, Kakinoki Y, Kobayashi N, Yamamoto S, Haseyama Y, Ando S, Kohgo Y, Teshima T
  • 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
• [Presentation] MULTICENTER CLINICAL STUDY TO EVALUATE A UTILITY OF FRET-BASED DRUG SENRITIVITY TEST THAT PREDICTS EARLY MOLECULAR RESPONSE IN NEWLY DIAGNOSED CML PATIENTS TREATED WITH NILOTINIB (2014)
  • Author(s): Kondo T, Ohba Y, Miyagishima T, Mori A, Iwasaki H, Shindo M, Kakinoki Y, Kobayashi N, Yamamoto S, Haseyama Y, Ando S, Fujimoto N, Nishio M, Kurosawa M, Kohgo Y, Teshima T
  • Organizer: European Association of Hematology 19th Congress
  • Place of Presentation: Milan ( Italy )
  • Year and Date: 2014-06-12 – 2014-06-15
• [Presentation] Impact of Genetic Alterlations and MRD Reduction on the Outcome of Intermediate-Risk Acute Myelogenous Leukemia. (2014)
  • Author(s): Kondo T, Fujisawa S, Sato A, Mori A, Imai K, Yamamoto S, Kakinoki Y, Miyagishima T, Tsutsumi Y, Haseyama Y, Wada Y, Kurosawa M, Iwasaki H, Imamura M, Teshima T
  • Organizer: 5th JSH International Symposium
  • Place of Presentation: アクトシティ浜松コングレスセンター（ 静岡県・浜松市 ）
  • Year and Date: 2014-05-24 – 2014-05-25