PMID- 33313091
OWN - NLM
STAT- PubMed-not-MEDLINE
LR  - 20220418
IS  - 2305-5839 (Print)
IS  - 2305-5847 (Electronic)
IS  - 2305-5839 (Linking)
VI  - 8
IP  - 21
DP  - 2020 Nov
TI  - Stromal cells promote chemoresistance of acute myeloid leukemia cells via 
      activation of the IL-6/STAT3/OXPHOS axis.
PG  - 1346
LID - 10.21037/atm-20-3191 [doi]
LID - 1346
AB  - BACKGROUND: Bone marrow stromal cells (BMSCs) are known to promote 
      chemoresistance in acute myeloid leukemia (AML) cells. However, the molecular 
      basis for BMSC-associated AML chemoresistance remains largely unexplored. 
      METHODS: The mitochondrial oxidative phosphorylation (OXPHOS) levels of AML cells 
      were measured by a Seahorse XFe24 cell metabolic analyzer. The activity of total 
      or mitochondrial signal transducer and transcription activator 3 (STAT3) in AML 
      cells was explored by flow cytometry and Western blotting. Real-time quantitative 
      PCR, Western blotting and enzyme-linked immunosorbent assay (ELISA) were used to 
      analyze expression of interleukin 6 (IL-6) in the human BMSC line HS-5, and IL-6 
      was knocked out in HS-5 cells by CRISPR/Cas9 system. RESULTS: In this study, we 
      observed that co-culturing with BMSCs heightened OXPHOS levels in AML cells, thus 
      promoting chemoresistance in these cells. HS-5 cell-induced upregulation of 
      OXPHOS is dependent on the activation of STAT3, especially on that of 
      mitochondrial serine phosphorylated STAT3 (pS-STAT3) in AML cells. The 
      relationship among pS-STAT3, OXPHOS, and chemosensitivity of AML cells induced by 
      BMSCs was demonstrated by the STAT3 activator and inhibitor, which upregulated 
      and downregulated the levels of mitochondrial pS-STAT3 and OXPHOS, respectively. 
      Intriguingly, AML cells remodeled HS-5 cells to secrete more IL-6, which 
      augmented mitochondrial OXPHOS in AML cells and stimulated their chemoresistance. 
      IL-6 knockout in HS-5 cells impaired the ability of these cells to activate 
      STAT3, to increase OXPHOS, or to promote chemoresistance in AML cells. 
      CONCLUSIONS: BMSCs promoted chemoresistance in AML cells via the activation of 
      the IL-6/STAT3/OXPHOS pathway. These findings exhibit a novel mechanism of 
      chemoresistance in AML cells in the bone marrow microenvironment from a metabolic 
      perspective.
CI  - 2020 Annals of Translational Medicine. All rights reserved.
FAU - Hou, Diyu
AU  - Hou D
AD  - Central Laboratory, Fujian Medical University Union Hospital, Fuzhou, China.
FAU - Wang, Bin
AU  - Wang B
AD  - Central Laboratory, Fujian Medical University Union Hospital, Fuzhou, China.
AD  - Clinical Laboratory, Fujian Children's Hospital, Fuzhou, China.
FAU - You, Ruolan
AU  - You R
AD  - Central Laboratory, Fujian Medical University Union Hospital, Fuzhou, China.
FAU - Wang, Xiaoting
AU  - Wang X
AD  - Central Laboratory, Fujian Medical University Union Hospital, Fuzhou, China.
FAU - Liu, Jingru
AU  - Liu J
AD  - Central Laboratory, Fujian Medical University Union Hospital, Fuzhou, China.
FAU - Zhan, Weiwu
AU  - Zhan W
AD  - Central Laboratory, Fujian Medical University Union Hospital, Fuzhou, China.
FAU - Chen, Ping
AU  - Chen P
AD  - Fujian Institute of Hematology, Fujian Provincial Key Laboratory on Hematology, 
      Fujian Medical University Union Hospital, Fuzhou, China.
FAU - Qin, Tiandi
AU  - Qin T
AD  - Central Laboratory, Fujian Medical University Union Hospital, Fuzhou, China.
FAU - Zhang, Xuehao
AU  - Zhang X
AD  - School of Medical Technology and Engineering, Fujian Medical University, Fuzhou, 
      China.
FAU - Huang, Huifang
AU  - Huang H
AD  - Central Laboratory, Fujian Medical University Union Hospital, Fuzhou, China.
LA  - eng
PT  - Journal Article
PL  - China
TA  - Ann Transl Med
JT  - Annals of translational medicine
JID - 101617978
PMC - PMC7723653
OTO - NOTNLM
OT  - IL-6/STAT3/OXPHOS axis
OT  - acute myeloid leukemia (AML)
OT  - chemosensitivity
OT  - stromal cells
COIS- Conflicts of Interest: All authors have completed the ICMJE uniform disclosure 
      form (available at http://dx.doi.org/10.21037/atm-20-3191). The authors have no 
      conflicts of interest to declare.
EDAT- 2020/12/15 06:00
MHDA- 2020/12/15 06:01
PMCR- 2020/11/01
CRDT- 2020/12/14 10:59
PHST- 2020/12/14 10:59 [entrez]
PHST- 2020/12/15 06:00 [pubmed]
PHST- 2020/12/15 06:01 [medline]
PHST- 2020/11/01 00:00 [pmc-release]
AID - atm-08-21-1346 [pii]
AID - 10.21037/atm-20-3191 [doi]
PST - ppublish
SO  - Ann Transl Med. 2020 Nov;8(21):1346. doi: 10.21037/atm-20-3191.