Exogenous mitochondrial transfer and endogenous mitochondrial fission facilitate AML resistance to OxPhos inhibition

• Project/Area Number: 18K07424
• Research Category: Grant-in-Aid for Scientific Research (C)
• Allocation Type: Multi-year Fund
• Section: 一般
• Review Section: Basic Section 52010:General internal medicine-related
• Research Institution: Juntendo University
• Principal Investigator: Tabe Yoko 順天堂大学, 大学院医学研究科, 教授 (70306968)
• Co-Investigator(Kenkyū-buntansha): 三井田 孝 順天堂大学, 大学院医学研究科, 教授 (80260545)
• Project Period (FY): 2018-04-01 – 2022-03-31
• Project Status: Completed (Fiscal Year 2021)
• Budget Amount: ¥4,420,000 (Direct Cost: ¥3,400,000、Indirect Cost: ¥1,020,000); Fiscal Year 2020: ¥1,040,000 (Direct Cost: ¥800,000、Indirect Cost: ¥240,000); Fiscal Year 2019: ¥1,430,000 (Direct Cost: ¥1,100,000、Indirect Cost: ¥330,000); Fiscal Year 2018: ¥1,950,000 (Direct Cost: ¥1,500,000、Indirect Cost: ¥450,000)
• Keywords: 急性骨髄性白血病 / 骨髄微小環境 / 酸化的リン酸化 / ミトコンドリア呼吸 / トンネルナノチューブ / マイトファジー / 白血病微小環境 / エネルギー代謝 / ミトコンドリア / tunneling nano tube / CAGE解析 / 細胞接着 / Mesenchymal Stem Cell / がん / 高齢者 / がん微小環境

Outline of Final Research Achievements

Acute myeloid leukemia (AML) cells are highly dependent on oxidative phosphorylation (OxPhos) for survival in the bone marrow (BM) microenvironment. We investigated how the BM microenvironment affects the response to OxPhos inhibition in AML. Mechanistically, OxPhos inhibition induced (1) transfer of mesenchymal stem cell (MSC)-derived mitochondria to AML cells via tunneling nanotubes under direct-contact coculture conditions, and (2) mitochondrial fission with an increase in functional mitochondria and mitophagy in AML cells. Mitochondrial fission is known to enhance cell migration, and we observed mitochondrial transport to the leading edge of protrusions of migrating AML cells toward MSCs by electron microscopy analysis. Our findings indicate an important role of exogenous mitochondrial trafficking from BM stromal cells to AML cells as well as endogenous mitochondrial fission and mitophagy in the compensatory adaptation of leukemia cells to energetic stress.

Academic Significance and Societal Importance of the Research Achievements

白血病は高齢者に多発する疾患で、治療後の再発が多い。これは、臓器予備能が低い高齢者に対して強力な抗がん剤治療を行うことができず、その結果、多数の白血病細胞が骨髄「微小環境」に生き残って治療抵抗性を獲得するためである。骨髄中の白血病細胞は、自ら作り上げた低栄養、低酸素状態の「白血病微小環境」の中で、独特のエネルギー代謝や低酸素環境への適応力を獲得する。微小環境中における白血病細胞のエネルギー制御について理解することは、白血病の再発防止に必須である。本研究では、白血病細胞の生存力の軸となる酸化的リン酸化の制御機構を解明した。

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] MD Anderson Cancer Center(米国)
• [Journal Article] Exogenous mitochondrial transfer and endogenous mitochondrial fission facilitate AML resistance to OxPhos inhibition. (2021)
  • Author(s): Saito K, Zhang Q, Yang H, Yamatani K, Ai T, Ruvolo V, Baran N, Cai T, Ma H, Jacamo R, Kuruvilla V, Imoto J, Kinjo S, Ikeo K, Moriya K, Suzuki K, Miida T, Kim YM, Vellano CP, Andreeff M, Marszalek JR, Tabe Y, Konopleva M.
  • Journal Title: Blood Adv Volume: 5 Issue: 20 Pages: 4233-4255
  • DOI: 10.1182/bloodadvances.2020003661
  • Peer Reviewed / Open Access / Int'l Joint Research
• [Journal Article] Break the lifeline of AML cells (2021)
  • Author(s): Yoko Tabe, Marina Konopleva
  • Journal Title: Blood Volume: 137 Issue: 25 Pages: 3465-3467
  • DOI: 10.1182/blood.2021011475
  • Peer Reviewed / Int'l Joint Research
• [Journal Article] Break the lifeline of AML cells (2021)
  • Author(s): Tabe Yoko、Konopleva Marina
  • Journal Title: Blood Volume: -
  • Peer Reviewed / Int'l Joint Research
• [Journal Article] Fatty Acid Metabolism, Bone Marrow Adipocytes, and AML (2020)
  • Author(s): Tabe Yoko、Konopleva Marina、Andreeff Michael
  • Journal Title: Frontiers in Oncology Volume: 10
  • DOI: 10.3389/fonc.2020.00155
  • Peer Reviewed / Open Access / Int'l Joint Research
• [Journal Article] 造血器腫瘍の治療標的としてのアミノ酸代謝経路 (2020)
  • Author(s): 田部 陽子
  • Journal Title: 血液内科 Volume: 81 Pages: 101-106
  • NAID: 40022315329
  • Int'l Joint Research
• [Journal Article] Amino acid metabolism in hematologic malignancies and the era of targeted therapy (2019)
  • Author(s): Tabe Y, Lorenzi PL, Konopleva M
  • Journal Title: Blood Volume: 134 Issue: 13 Pages: 1014-1023
  • DOI: 10.1182/blood.2019001034
  • Peer Reviewed / Open Access / Int'l Joint Research
• [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
• [Presentation] Diverse mechanisms of resistance to Decitabine and Venetoclax therapy in newly diagnosed and relapsed/refractory AML inferred by transcriptome analysis. (2021)
  • Author(s): Kotoko Yamatani, Yoko Tabe, Abhishek Maiti, Tomohiko Ai, Kaori Saitoh, Kazuhiro R. Nitta, Sonoko Kinjo, Kazuho Ikeo, Takashi Miida, Courtney D. DiNardo, Su Xiaoping, Marina Konopleva
  • Organizer: 63th American Society of Hematology Annual Meeting
  • Int'l Joint Research
• [Presentation] BCL2A1: a novel target in refractory acute myeloid leukemia with FLT3-ITD/D835 dual mutations (2020)
  • Author(s): Kotoko Yamatani, Tomohiko Ai, Kaori Saitoh, Haeun Yang, Sonoko Kinjo, Kazuho Ikeo, Vivian Ruvolo, Po Yee Mak, Hironori Harada, Kazuhiro Katayama, Yoshikazu Sugimoto, Takashi Miida, Marina Konopleva, Weiguo Zhang, Bing Z. Carter, Yoshihide Hayashizaki, Michael Andreeff, Yoko Tabe.
  • Organizer: American Society of Hematology Annual Meeting
  • Int'l Joint Research
• [Presentation] The direct interactions with bone marrow microenvronment confer resistance to the inhibition of Oxidative Phosphorylation in AML (2020)
  • Author(s): Yoko Tabe, Kaori Saitoh, Kotoko Yamatani, Haeun Yang, Rodrigo Jacamo, Helen Ma, Vivian Ruvolo3, Qi Zhang, Vinitha Kuruvilla, Natalia Baran, Junichi Imoto, Kazuho Ikeo5, Kaori Moriya, Yuko Murakami-Tonami, Koya Suzuki, Takashi Miida, Michael Andreeff, Christopher P. Vellano, Joseph R. Marszalek, Marina Konopleva
  • Organizer: American Society of Hematology Annual Meeting
  • Int'l Joint Research
• [Presentation] Fatty acid metabolism and bone marrow adipocytes in AML (2019)
  • Author(s): Yoko Tabe
  • Organizer: ESH 3rd Scientific Workshop on Haematological Tumour Microenvironment and its Therapeutic Targeting
  • Int'l Joint Research / Invited
• [Presentation] Tunneling NanoTubes formation as a mechanism of microenvironment-induced resistance to OxPhos inhibition in AML (2019)
  • Author(s): Yoko Tabe
  • Organizer: Annual GAP Conference
  • Int'l Joint Research / Invited
• [Presentation] Cell adhesion to BM stromal cells confers resistance to OXPHOS inhibition in AML (2019)
  • Author(s): Haeun Yang, Kaori Saitoh, Junichi Imoto, Kazuho Ikeo, Takashi Miida, Yoko Tabe
  • Organizer: 81th Annual Meeting of the Japanese Society of Hematology
• [Presentation] Metabolic inhibition and mitochondrial transfer caused by OXPHOS inhibition in AML (2019)
  • Author(s): Kaori Saitoh, Haeun Yang, Yuko Murakami-Tonami Y, Koya Suzuki, Takashi Miida. Yoko Tabe
  • Organizer: 81th Annual Meeting of the Japanese Society of Hematology
• [Presentation] Molecular mechanisms of resistance to OxPhos inhibition in AML (2019)
  • Author(s): Haeun Yang, Kaori Saitoh, Junichi Imoto, Kazuho Ikeo, Takashi Miida, Yoko Tabe
  • Organizer: 24th Annual Meeting of Japan Society of Gene and Cell Therapy
• [Presentation] OxPhos inhibition induces formation of tunneling nanotubes in AML cells and facilitates mitochondrial transfer from BM stroma to AML that contributes to microenvironment-mediated drug-resistance of AML (2019)
  • Author(s): Haeun Yang, Yoko Tabe, Kaori Saitoh, Kotoko Yamatani, Rodrigo Jacamo, Helen Ma, Vivian Ruvolo, Qi Zhang, Vinitha Kuruvilla, Natalia Baran, Junichi Imoto, Kazuho Ikeo, Kaori Moriya, Yuko Murakami-Tonami, Koya Suzuki, Takashi Miida, Michael Andreeff, Christopher P. Vellano, Joseph R. Marszalek, Marina Konopleva
  • Organizer: 61th American Society of Hematology Annual Meeting
  • Int'l Joint Research
• [Presentation] Inhibiting mitochondria function by Bcl-2 inhibitor venetoclax and complex I inhibitor IACS-010759 eliminate leukemia cells in pre-clinical AML models (2019)
  • Author(s): Qi Zhang, Alessia Lodi, Lina Han, Tianyu Cai, Vinitha M. Kuruvilla, Antonio Cavazos, Helen Ma, Yoko Tabe, Joseph R. Marszalek Stefano Tiziani, Marina Konopleva
  • Organizer: 61th American Society of Hematology Annual Meeting
  • Int'l Joint Research
• [Presentation] Tunneling nanotubes formation as a mechanism of microenvironment-induced resistance to OxPhos inhibition in AML (2019)
  • Author(s): Yoko Tabe, Haeun Yang, Kaori Saito, Rodrigo Jacamo, Helen Ma, Vivian Ruvolo, Junichi Imoto , Kazuho Ikeo, Kotoko Yamatani, Takashi Miida, Yoshihide Hayashizaki, Michael Andreeff, Joseph Marszalek, Marina Konopleva
  • Organizer: MD Anderson Cancer Center GAP 2019 conference
  • Int'l Joint Research / Invited
• [Presentation] Cell adhesion to mesenchymal stem cells mediates resistance to oxidative phosphorylation inhibition in acute myeloid leukemia (2019)
  • Author(s): Haeun Yang, Kaori Saitoh, Junichi Imoto, Kazuho Ikeo, Takashi Miida, Yoko Tabe
  • Organizer: International Symposium on Technical Innovations in Laboratory Hematology
  • Int'l Joint Research
• [Presentation] Mitochondrial transfer confers microenvironment-mediated resistance to OxPhos inhibition in AML. (2018)
  • Author(s): Yang H, Tabe Y, Saitoh K, Jacamo R, Ma H, Ruvolo V, Imoto J, Ikeo K, Mogushi K, Hosoya M, Yamaguchi S, Yamatani K, Murakami-Tonami Y, Suzuki K, Miida T, Andreeff M, Marszalek JR, Konopleva M.
  • Organizer: 60th American Society of Hematology Annual Meeting and Exposition
  • Int'l Joint Research
• [Presentation] Novel Oxidative phosphorylation inhibitor IACS-010759 inhibits p38MAPK-NFkB signaling pathways. (2018)
  • Author(s): Tabe Y, Yang H, Sekihara K, Saitoh K, Ma H, Ruvolo V, Imoto J, Ikeo K, Mogushi K, Hosoya M, Hayashizaki Y, Yamanaka Y, Miida T, Andreeff M, Marszalek JR, Konopleva M.
  • Organizer: GAP 2018 Conference
  • Int'l Joint Research