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Author Spotlight: Analyzing Bone Marrow Microenvironment in Murine Hematological Malignancies
06:33

Author Spotlight: Analyzing Bone Marrow Microenvironment in Murine Hematological Malignancies

Published on: November 10, 2023

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Bone marrow microenvironment drives AML cell OXPHOS addiction and AMPK inhibition to resist chemotherapy

Ruolan You1, Diyu Hou1, Bin Wang1

  • 1Central Laboratory, Fujian Medical University Union Hospital, Fuzhou, Fujian, China.

Journal of Leukocyte Biology
|December 20, 2021
PubMed

Insights

The bone marrow microenvironment promotes AML chemoresistance by increasing oxidative phosphorylation and inhibiting AMPK, which activates mTORC1. Targeting this pathway may overcome resistance in acute myeloid leukemia.

Area of Science:

  • Oncology
  • Cell Metabolism
  • Molecular Biology

Background:

  • The bone marrow microenvironment (BMM) is crucial in acute myeloid leukemia (AML) chemoresistance.
  • Energy metabolism reprogramming is a key feature of cancer cells.
  • 5'-Adenosine monophosphate-activated protein kinase (AMPK) regulates cellular energy and suppresses mTORC1 activity.

Purpose of the Study:

  • To investigate the role of the AMPK-mTORC1 pathway in mediating BMM-induced AML chemoresistance.
  • To understand how AML cell energy metabolism is reprogrammed by the stromal niche.

Main Methods:

  • Utilized a co-culture system simulating BMM-AML cell interactions.
  • Assessed chemotherapy sensitivity, oxidative phosphorylation (OXPHOS) activity, and mitochondrial ATP synthesis in AML cells.
  • Employed an in vivo AML mouse model with genetic targeting of AMPK.

Main Results:

  • Stromal contact decreased AML sensitivity to chemotherapy.
  • AML cells exhibited increased OXPHOS activity and ATP production.
  • Increased OXPHOS and ATP inhibited AMPK, leading to mTORC1 activation and chemoresistance.
  • AMPK depletion in vivo accelerated AML progression and reduced drug sensitivity.

Conclusions:

  • AML cells adapt their energy metabolism, increasing OXPHOS and inhibiting AMPK, to resist chemotherapy within the BMM.
  • The observed AMPK inhibition and subsequent mTORC1 activation are key mechanisms of BMM-induced chemoresistance.
  • Targeting increased OXPHOS and AMPK inhibition presents a potential therapeutic strategy to overcome BMM-mediated chemoresistance in AML.
Keywords:
AMPK-mTORC1 pathwayATPOXPHOSacute myeloid leukemiachemotherapy resistance

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