Bone marrow microenvironment drives AML cell OXPHOS addiction and AMPK inhibition to resist chemotherapy. Issue 2 (20th December 2021)

• Record Type: Journal Article
• Authors: You, Ruolan; Hou, Diyu; Wang, Bin; Liu, Jingru; Wang, Xiaoting; Xiao, Qirong; Pan, Zhipeng; Li, Dongliang; Feng, Xiaoming; Kang, Lixia; Chen, Ping; Huang, Huifang
• Is Part Of: Journal of leukocyte biology. Volume 112:Issue 2(2022)
• Page Start: 299
• Page End: 311
• Publication Date: 2021-12-20
• Subjects: acute myeloid leukemia -- AMPK-mTORC1 pathway -- ATP -- chemotherapy resistance -- OXPHOS; Leucocytes -- Periodicals; Reticulo-endothelial system -- Periodicals; 571.96
• DOI: 10.1002/JLB.6A0821-409RR
• Languages: English
• ISSNs: 0741-5400

Abstract

Abstract: The stromal niche plays a pivotal role in AML chemoresistance and energy metabolism reprogramming is a hallmark of a tumor. 5′-Adenosine monophosphate-activated protein kinase (AMPK) is an important energy sensor suppressing mammalian target of rapamycin complex 1 (mTORC1) activity. However, the role of AMPK-mTORC1 pathway on connecting AML cell energy metabolism reprogramming and chemoresistance induced by the bone marrow microenvironment (BMM) is not defined. Here, with a co-culture system that simulates the interaction between BMM and AML cells, it is shown that stromal contact led to a decreased sensitivity to chemotherapy accompanied by an increase of oxidative phosphorylation (OXPHOS) activity and mitochondrial ATP synthesis in AML cells. The increased OXPHOS activity and excessive ATP production promoted chemoresistance of AML cells through inhibiting AMPK activity and in turn activating mTORC1 activity. In an in vivo AML mouse model, depletion of AMPK activity with genetic targeting promoted AML progression and reduced their sensitivity to chemotherapeutic drugs. Collectively, AML cells' acquired increased OXPHOS activity as well as AMPK inhibition could be therapeutically exploited in an effort to overcome BMM-mediated chemoresistance. Graphical Abstract: Stromal contact renders AML cells chemoresistance by promoting AML cells' OXPHOS activity and OXPHOS's mechanism of action involves AMPK-mTORC1 pathway.