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

2018 Fiscal Year Final Research Report

• 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
• 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

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.

Free Research Field

臨床検査医学

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。