Survival of acute monocytic leukemia cells is driven by activation of fatty acid oxidation in adipocytes rich bone marrow microenvironment
Project/Area Number |
15K08653
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Research Category |
Grant-in-Aid for Scientific Research (C)
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Allocation Type | Multi-year Fund |
Section | 一般 |
Research Field |
Laboratory medicine
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Research Institution | Juntendo University |
Principal Investigator |
Tabe Yoko 順天堂大学, 医学(系)研究科(研究院), 特任教授 (70306968)
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Co-Investigator(Kenkyū-buntansha) |
三井田 孝 順天堂大学, 医学(系)研究科(研究院), 教授 (80260545)
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Project Period (FY) |
2015-04-01 – 2019-03-31
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Project Status |
Completed (Fiscal Year 2018)
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Budget Amount *help |
¥4,810,000 (Direct Cost: ¥3,700,000、Indirect Cost: ¥1,110,000)
Fiscal Year 2017: ¥1,170,000 (Direct Cost: ¥900,000、Indirect Cost: ¥270,000)
Fiscal Year 2016: ¥1,560,000 (Direct Cost: ¥1,200,000、Indirect Cost: ¥360,000)
Fiscal Year 2015: ¥2,080,000 (Direct Cost: ¥1,600,000、Indirect Cost: ¥480,000)
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Keywords | 高齢者白血病 / 骨髄微小環境 / 脂肪酸代謝 / 骨髄脂肪細胞 / 急性骨髄単球性白血病 / 急性単球性白血病 / アポトーシス / AraC / AvocatinB / AMPK / ATF4 / 急性骨髄性白血病 / 脂肪酸β酸化 / トランスクリプトーム解析 |
Outline of Final Research Achievements |
In acute monocytic leukemia (AMoL) cells, the prevention of spontaneous apoptosis by BM adipocytes was associated with an increase in fatty acid β-oxidation (FAO). The novel FAO inhibitor avocatin B induced apoptosis and growth inhibition in mono-cultured AML cells. In AML cells co-cultured with BM adipocytes, FAO inhibition with avocatin B caused adaptive stimulation of free fatty acid (FFA) uptake through upregulation of FABP4 mRNA, enhanced glucose uptake and switch to glycolysis. These changes facilitate the protection of AMoL cells from avocatin B induced apoptosis in the presence of BM adipocytes. However, the combination treatment of avocatin B and cytarabine (AraC) increased reactive oxygen species and demonstrated highly synergistic effects on AMoL cells under BM adipocyte co-culture condition. These findings highlight the potential for combination regimens of AraC and FAO inhibitors that target bone marrow-resident chemoresistant AMoL cells.
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Academic Significance and Societal Importance of the Research Achievements |
臓器予備能が低下した高齢者のがん治療の選択肢は少なく予後は不良でなる。急性骨髄性白血病もその例外ではなく、副作用の少ない新しい治療戦略の開発が求められている。本研究では、脂肪成分が豊富な高齢者骨髄(黄色髄 / 脂肪髄)が難治性のAMoL細胞の生存に関与する分子機序の一端を明らかにした。本研究で得られた知見は、白血病にとどまらず、将来の高齢者のがん代謝制御治療に有用な情報を提供する。
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Report
(5 results)
Research Products
(36 results)
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[Journal Article] Inhibition of FAO in AML co-cultured with BM adipocytes: mechanisms of survival and chemosensitization to cytarabine.2018
Author(s)
Tabe Y, Saitoh K, Yang H, Sekihara K, Yamatani K, Ruvolo V, Taka H, Kaga N, Kikkawa M, Arai H, Miida T, Andreeff M, Spagnuolo PA, Konopleva M.
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Journal Title
Sci Rep
Volume: 8
Issue: 1
Pages: 16837-16837
DOI
Related Report
Peer Reviewed / Open Access / Int'l Joint Research
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[Journal Article] Targeting mantle cell lymphoma metabolism and survival through simultaneous blockade of mTOR and nuclear transporter exportin-1.2017
Author(s)
Sekihara K, Saitoh K, Han L, Ciurea S, Yamamoto S, Kikkawa M, Kazuno S, Taka H, Kaga N, Arai H, Miida T, Andreeff M, Konopleva M, Tabe Y.
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Journal Title
Oncotarget
Volume: in press
Issue: 21
Pages: 34552-34564
DOI
Related Report
Peer Reviewed / Open Access / Int'l Joint Research / Acknowledgement Compliant
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[Journal Article] Bone Marrow Adipocytes Facilitate Fatty Acid Oxidation Activating AMPK and a Transcriptional Network Supporting Survival of Acute Monocytic Leukemia Cells.2017
Author(s)
Tabe Y, Yamamoto S, Saitoh K, Sekihara K, Monma N, Ikeo K, Mogushi K, Shikami M, Ruvolo V, Ishizawa J, Hail N Jr, Kazuno S, Igarashi M, Matsushita H, Yamanaka Y, Arai H, Nagaoka I, Miida T, Hayashizaki Y, Konopleva M, Andreeff M.
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Journal Title
Cancer Res.
Volume: 77
Issue: 6
Pages: 1453-1464
DOI
Related Report
Peer Reviewed / Int'l Joint Research / Acknowledgement Compliant
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[Journal Article] Pancreatic lipase activity in overnight effluent predicts high transport status in peritoneal dialysis patients.2016
Author(s)
Idei M, Tabe Y, Hamada C, Miyake K, Takemura H, Io H, Wakita M, Horii T, Tomino Y, Ohsaka A, Miida T.
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Journal Title
Clin Chim Acta
Volume: 462
Pages: 65-70
DOI
Related Report
Peer Reviewed
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[Journal Article] ATF4 induction through an atypical integrated stress response to ONC201 triggers p53-independent apoptosis in hematological malignancies.2016
Author(s)
Ishizawa J, Kojima K, Chachad D, Ruvolo P, Ruvolo V, Jacamo RO, Borthakur G, Mu H, Zeng Z, Tabe Y, Allen JE, Wang Z, Ma W, Lee HC, Orlowski R, Sarbassov dos D, Lorenzi PL, Huang X, Neelapu SS, McDonnell T, Miranda RN, Wang M, Kantarjian H, Konopleva M, Davis RE, Andreeff M.
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Journal Title
Sci Signal.
Volume: 9
Issue: 415
DOI
Related Report
Peer Reviewed / Int'l Joint Research
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[Journal Article] Ribosomal biogenesis and translational flux inhibition by the selective inhibitor of nuclear export (SINE) XPO1 antagonist KPT-185.2015
Author(s)
Yoko Tabe, Kensuke Kojima, Shinichi Yamamoto, Kazumasa Sekihara, Hiromichi Matsushita, Richard Eric Davis, Zhiqiang Wang, Wencai Ma, Jo Ishizawa, Saiko Kazuno, Michael Kauffman, Sharon Shacham, Tsutomu Fujimura, Takashi Ueno, Takashi Miida, Michael Andreef
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Journal Title
PLoS One
Volume: 10
Issue: 9
Pages: e0137210-e0137210
DOI
Related Report
Peer Reviewed / Open Access / Int'l Joint Research
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[Journal Article] The novel combination of dual mTOR inhibitor AZD2014 and pan-PIM inhibitor AZD1208 inhibits growth in acute myeloid leukemia via HSF pathway suppression.2015
Author(s)
Harada M, Benito J, Yamamoto S, Kaur S, Arslan D, Ramirez S, Jacamo R, Platanias L, Matsushita H, Fujimura T, Kazuno S, Kojima K, Tabe Y, Konopleva M.
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Journal Title
Oncotarget
Volume: 6
Issue: 35
Pages: 37930-37947
DOI
Related Report
Peer Reviewed / Int'l Joint Research
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[Presentation] Inhibition of FAO in AML co-cultured with BM adipocytes: mechanisms of survival and chemosensitization to cytarabine.2017
Author(s)
Yoko Tabe, Kazumasa Sekihara, Haeun Yang, Kaori Saito, Vivian Ruvolo, Hikari Taka, Naoko Kaga, Takashi Miida, Michael Andreeff, Paul A Spagnuolo, Marina Konopleva.
Organizer
59th American Society of Hematology Annual Meeting and Exposition
Related Report
Int'l Joint Research
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[Presentation] XPO1 Inhibition Targets Transcriptional Vulnerability of FLT3-ITD+D835 Double Mutant AML through p53 Accumulation and Inhibition of Oncogenic Transcription Factors: Lesson Learned from Cage Sequencing of Primary AML Cells.2017
Author(s)
Kotoko Yamatani, Yoko Tabe, Kazumasa Sekihara, Haeun Yang, Kaori Saito, Weiguo Zhang, Kazuho Ikeo , Sonoko Kinjo, Kaoru Mogushi, Masaki Hosoya1, Yoshihide Hayashizaki, Yasunari Yamanaka, Hironori Harada, Takashi Miida, Marina Konopleva, and Michael Andreeff
Organizer
59th American Society of Hematology Annual Meeting and Exposition
Related Report
Int'l Joint Research
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[Presentation] Novel Oxidative Phosphorylation Inhibitor Iacs-010759 Induces AMPK-Dependent Apoptosis of AML Cells.2017
Author(s)
Haeun Yang, Yoko Tabe, Kazumasa Sekihara, Kaori Saito, Helen Ma, Vivian Ruvolo, Junichi Imoto, Kazuho Ikeo, Kaoru Mogushi, Masaki Hosoya1, Yoshihide Hayashizaki, Yasunari Yamanaka, Takashi Miida, Michael Andreeff, Joseph R Marszalek, and Marina Konopleva
Organizer
59th American Society of Hematology Annual Meeting and Exposition
Related Report
Int'l Joint Research
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[Presentation] BCL-2 Antagonist ABT-199 Combined with Complex I Inhibitor Iacs-010759 Blocks Mitochondrial Respiration and Facilitates Anti-Leukemia Efficacy in Pre-Clinical AML Models.2017
Author(s)
Qi Zhang, Lina Han, Tianyu Cai, Vinitha Mary Kuruvilla, Antonio Cavazos, Helen Ma, Venkata Lokesh Battula, Natalia Baran, Karine Harutyunyan, Michael Andreeff, Yoko Tabe, Joseph R Marszalek, Marina Konopleva
Organizer
9th American Society of Hematology Annual Meeting and Exposition
Related Report
Int'l Joint Research
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[Presentation] Cap analysis of gene expression (CAGE) sequencing reveals alterations of the transcriptional signatures of FLT3-ITD with secondary D835 TKD mutations in acute myeloid leukemia.2016
Author(s)
Yoko Tabe, Kazumasa Sekihara, Kaori Saitoh, Norikazu Monma, Kazuho Ikeo, Bogumil Kaczkowski, Weiguo Zhang, Yasunari Yamanaka, Takashi Miida, Neil P. Shah, Hironori Harada, Yoshihide Hayashizaki, Marina Konopleva, Michael Andreeff.
Organizer
58th American Society of Hematology (ASH) Annual Meeting and Exposition.
Place of Presentation
San Diego, USA
Year and Date
2016-12-03
Related Report
Int'l Joint Research
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[Presentation] Inactivating Heat Shock Factor 1 (HSF1) in Acute Myeloid Leukemia By Pharmacological Inhibition of eIF4a: A Promising Therapeutic Approach.2015
Author(s)
Jo Ishizawa, Rodrigo Omar Jacamo, Kensuke Kojima, Dhruv Chachad, Vivian Ruvolo, Peter Ruvolo, Weiguo Zang, Yoko Tabe, Marina Konopleva, William Devine, Susan Lindquist, John A Porco, Luke Whitesell, Michael Andreeff:
Organizer
57th American Society of Hematology (ASH) Annual Meeting and Exposition.
Place of Presentation
Orlando (アメリカ)
Year and Date
2015-12-05
Related Report
Int'l Joint Research
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[Presentation] Combined Targeting of JAK2 with a Type II JAK2 Inhibitor and mTOR with a TOR Kinase Inhibitor Constitutes Synthetic Activity in JAK2-Driven Ph-like Acute Lymphoblastic Leukemia2015
Author(s)
Ce Shi, Lina Han, Qi Zhang, Kathryn G. Roberts, Eugene Park, Yoko Tabe, Rodrigo Omar Jacamo, Hong Mu, Shuo-Chieh Wu, Jin Zhou, Helen Ma1, Zhihong Zeng, Nitin Jain, Elias J Jabbour, Markus Muschen1, Sarah K Tasian, Charles G. Mullighan, David M. Weinstock, David Fruman, Marina Konopleva,.
Organizer
57th American Society of Hematology (ASH) Annual Meeting and Exposition.
Place of Presentation
Orlando (アメリカ)
Year and Date
2015-12-05
Related Report
Int'l Joint Research
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[Presentation] ONC201 Induces p53-Independent Apoptosis and Abrogates Stem Cell Function in Hematological Malignancies By Induction of ATF4 through Integrated Stress Response2015
Author(s)
Ishizawa J, Kojima K, Chachad D, Ruvolo P, Ruvolo V, Jacamo RO, Borthakur G, Mu H, Zeng Z, Tabe Y, Allen J, Wang Z, Ma W, Lee H, Orlowski RZ, Sarbassov DD, Neelapu SS, McDonnell TJ, Miranda RN, Wang M, Kantarjian HM, Konopleva M, Eric Davis R, Andreeff M:
Organizer
57th American Society of Hematology (ASH) Annual Meeting and Exposition.
Place of Presentation
Orlando (アメリカ)
Year and Date
2015-12-05
Related Report
Int'l Joint Research
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