Survival of acute monocytic leukemia cells is driven by activation of fatty acid oxidation in adipocytes rich bone marrow microenvironment

• Project/Area Number: 15K08653
• Research Category: Grant-in-Aid for Scientific Research (C)
• Allocation Type: Multi-year Fund
• Section: 一般
• Research Field: Laboratory medicine
• 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)
• 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)
• Project Period (FY): 2015-04-01 – 2019-03-31
• Project Status: Completed (Fiscal Year 2018)
• Budget Amount: ¥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)
• 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.

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。

Research Products

• [Int'l Joint Research] MD Anderson Cancer Center(米国)
• [Int'l Joint Research] MD Anderson Cancer Center(米国)
• [Int'l Joint Research] MD Anderson Cancer Center(米国)
• [Int'l Joint Research] MDAnderson Cancer Center(米国)
• [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.
  • Journal Title: Sci Rep Volume: 8 Issue: 1 Pages: 16837-16837
  • DOI: 10.1038/s41598-018-35198-6
  • Peer Reviewed / Open Access / Int'l Joint Research
• [Journal Article] An inhibitor of oxidative phosphorylation exploits cancer vulnerability (2018)
  • Author(s): Molina Jennifer R.、Tabe Yoko、Draetta Giulio F.、Heffernan Timothy P.、Konopleva Marina、Jones Philip、Di Francesco M. Emilia、Marszalek Joseph R.et al.
  • Journal Title: Nature Medicine Volume: 24 Issue: 7 Pages: 1036-1046
  • DOI: 10.1038/s41591-018-0052-4
  • Peer Reviewed / Open Access / Int'l Joint Research
• [Journal Article] Inhibition of mTORC1/C2 signaling improves anti-leukemia efficacy of JAK/STAT blockade in <i>CRLF2</i> rearranged and/or <i>JAK</i> driven Philadelphia chromosome&#x2013;like acute B-cell lymphoblastic leukemia (2018)
  • Author(s): Zhang Qi、Cai Tianyu、Cavazos Antonio、Tabe Yoko、et al.
  • Journal Title: Oncotarget Volume: 9 Issue: 8 Pages: 8027-8041
  • DOI: 10.18632/oncotarget.24261
  • Peer Reviewed / Open Access / Int'l Joint Research
• [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.
  • Journal Title: Oncotarget Volume: in press Issue: 21 Pages: 34552-34564
  • DOI: 10.18632/oncotarget.16602
  • Peer Reviewed / Open Access / Int'l Joint Research / Acknowledgement Compliant
• [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.
  • Journal Title: Cancer Res. Volume: 77 Issue: 6 Pages: 1453-1464
  • DOI: 10.1158/0008-5472.can-16-1645
  • Peer Reviewed / Int'l Joint Research / Acknowledgement Compliant
• [Journal Article] Neutrophil extracellular traps induce IL-1β production by macrophages in combination with lipopolysaccharide. (2017)
  • Author(s): Hu Z, Murakami T, Tamura H, Reich J, Kuwahara-Arai K, Iba T, Tabe Y, Nagaoka I.
  • Journal Title: Int J Mol Med. Volume: in press Issue: 3 Pages: 549-558
  • DOI: 10.3892/ijmm.2017.2870
  • Peer Reviewed / Open Access / Int'l Joint Research
• [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.
  • Journal Title: Clin Chim Acta Volume: 462 Pages: 65-70
  • DOI: 10.1016/j.cca.2016.08.009
  • Peer Reviewed
• [Journal Article] Impact of Clotting Condition on the Measurement of Circulating MicroRNAs in Serum. (2016)
  • Author(s): Hayashi K, Tabe Y, Miida T.
  • Journal Title: Clin Lab. Volume: 62 Pages: 471-475
  • Peer Reviewed
• [Journal Article] Comparison of prothrombin time tests used in the monitoring of edoxaban and their evaluation as indicators of the reversal effect. (2016)
  • Author(s): Iba T, Emmi M, Hiki M, Nagayama M, Aihara K, Tabe Y, Yuri M, Ohsaka A.
  • Journal Title: Int J Hematol. Volume: 103 Issue: 6 Pages: 665-672
  • DOI: 10.1007/s12185-016-1975-5
  • Peer Reviewed
• [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.
  • Journal Title: Sci Signal. Volume: 9 Issue: 415
  • DOI: 10.1126/scisignal.aac4380
  • Peer Reviewed / Int'l Joint Research
• [Journal Article] Role of microenvironment in resistance to therapy in AML. (2015)
  • Author(s): Tabe Y, Konopleva M.
  • Journal Title: Curr Hematol Malig Rep. Volume: 10 Issue: 2 Pages: 96-103
  • DOI: 10.1007/s11899-015-0253-6
  • Peer Reviewed / Int'l Joint Research
• [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
  • Journal Title: PLoS One Volume: 10 Issue: 9 Pages: e0137210-e0137210
  • DOI: 10.1371/journal.pone.0137210
  • Peer Reviewed / Open Access / Int'l Joint Research
• [Journal Article] Expression, function, and targeting of the nuclear exporter chromosome region maintenance 1 (CRM1) protein. (2015)
  • Author(s): Ishizawa J, Kojima K, Hail N Jr, Tabe Y, Andreeff M.
  • Journal Title: Pharmacol Ther. Volume: 153 Pages: 25-35
  • DOI: 10.1016/j.pharmthera.2015.06.001
  • Peer Reviewed / Int'l Joint Research
• [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.
  • Journal Title: Oncotarget Volume: 6 Issue: 35 Pages: 37930-37947
  • DOI: 10.18632/oncotarget.6122
  • Peer Reviewed / Int'l Joint Research
• [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
  • Int'l Joint Research
• [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
  • Int'l Joint Research
• [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
  • Int'l Joint Research
• [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
  • Int'l Joint Research
• [Presentation] Bone marrow adipocytes facilitate fatty acid oxidation activating AMPK and a transcriptional network supporting survival of acute monocytic leukemia cells. (2017)
  • Author(s): Yoko Tabe
  • Organizer: Annual GAP Conference
  • Int'l Joint Research
• [Presentation] Novel fatty acid oxidation inhibitor avocatinB induces AMPK-dependent apoptosis of AML cells co-cultured with BM-adipocytes. (2016)
  • Author(s): Yoko Tabe, Kazumasa Sekihara, Kaori Saitoh, Vivian Ruvolo, Takashi Miida, Michael Andreeff, Paul A. Spagnuolo, Marina Konopleva.
  • Organizer: 58th American Society of Hematology (ASH) Annual Meeting and Exposition.
  • Place of Presentation: San Diego, USA
  • Year and Date: 2016-12-03
  • Int'l Joint Research
• [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
  • Int'l Joint Research
• [Presentation] The simultaneous blockade of mTOR and nuclear transporter exportin-1 induces synergistic antitumor effect through pro-survival metabolism in mantle cell lymphoma. (2016)
  • Author(s): Kazumasa Sekihara, Kaori Saitoh, Takashi Miida, Michael Andreeff, Marina Konopleva, Yoko Tabe.
  • Organizer: Society of Hematologic Oncology Fourth Annual Meeting.
  • Place of Presentation: Houston, USA
  • Year and Date: 2016-09-07
  • Int'l Joint Research
• [Presentation] Novel flowcytometry-based approach to detect tumor cells in body fluid using Sysmex automated hematology analyzer. (2016)
  • Author(s): Akimichi Ohsaka, Hiroyuki Takemura, Toshihiro Takahashi, Konobu Kimura, Aya Konishi, Takashi Horii, Takashi Miida, Yoko Tabe.
  • Organizer: 68th AACC Annual Scientific Meeting & Clinical Lab Expo.
  • Place of Presentation: Philadelphia, USA
  • Year and Date: 2016-07-31
  • Int'l Joint Research
• [Presentation] Novel flowcytometry-based approach of tumor cells detection in body fluid using Sysmex automated hematology analyzer. (2016)
  • Author(s): Yoko Tabe, Toshihiro Takahashi, Hiroyuki Takemura, Konobu Kimura, Aya Konishi, Takashi Horii, Takashi Miida, Akimichi Ohsaka.
  • Organizer: 29th International Symposium on Technological Innovations in Laboratory Hematology.
  • Place of Presentation: Milano, Italy
  • Year and Date: 2016-05-12
  • Int'l Joint Research
• [Presentation] mTOR kinase inhibitor AZD-2014 enhances the antitumor effects of XPO1 antagonist KPT-185 in mantle cell lymphoma. (2015)
  • Author(s): Kazumasa Sekihara, Shinichi Yamamoto, Mika Kikkawa, Hikari Taka, Naoko Kaga, Hiromichi Matsushita, Takashi Miida, Michael Andreeff, Marina Konopleva, Yoko Tabe
  • Organizer: European Society for Medical Oncology (ESMO) Asia 2015 Congress
  • Place of Presentation: Singapore （シンガポール）
  • Year and Date: 2015-12-18
  • Int'l Joint Research
• [Presentation] Novel FAO inhibitor avocatin B induces apoptosis of acute monocytic leukemia cells in adipocyte co-culture system via ER stress and ATF4 activation. (2015)
  • Author(s): Yoko Tabe, Shinichi Yamamoto, Mika Kikkawa, Hikari Taka, Naoko Kaga, Kaoru Mogushi, Hiromichi Matsushita, Takashi Miida, Michael Andreeff, Paul A. Spagnuolo6 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
  • Int'l Joint Research
• [Presentation] Cap analysis of gene expression (CAGE) sequencing reveals alterations of the transcript signatures in acute monocytic leukemia cells by fatty acid oxidation inhibition (2015)
  • Author(s): Yoko Tabe, Marina Konopleva, Norikazu Monma, Kazuho Ikeo, Kaoru Mogushi, Yasunari Yamanaka, Hiromichi Matsushita, Takashi Miida, Yoshihide Hayashizaki, 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
  • Int'l Joint Research
• [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
  • Int'l Joint Research
• [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 Leukemia (2015)
  • 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
  • Int'l Joint Research
• [Presentation] ONC201 Induces p53-Independent Apoptosis and Abrogates Stem Cell Function in Hematological Malignancies By Induction of ATF4 through Integrated Stress Response (2015)
  • 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
  • Int'l Joint Research
• [Remarks] 順天堂大学大学院医学研究科 臨床病態検査医学 業績
  • URL: http://www.juntendo.ac.jp/graduate/laboratory/labo/byotaikaiseki/k6.html
• [Remarks] 順天堂大学医学部 臨床検査医学講座 業績
  • URL: http://www.juntendo.ac.jp/med/labo/rinsyo_byori3.html