Bone Marrow Mesenchymal Stem Cells Support Acute Myeloid Leukemia Bioenergetics and Enhance Antioxidant Defense and Escape from Chemotherapy

Dorian Forte, María García-Fernández, Abel Sánchez-Aguilera, Vaia Stavropoulou, Claire Fielding, Daniel Martín-Pérez, Juan Antonio López, Ana S.H. Costa, Laura Tronci, Efterpi Nikitopoulou, Michael Barber, Paolo Gallipoli, Ludovica Marando, Carlos López Fernández de Castillejo, Alexandar Tzankov, Sabine Dietmann, Michele Cavo, Lucia Catani, Antonio Curti, Jesús VázquezChristian Frezza, Brian J. Huntly, Juerg Schwaller, Simón Méndez-Ferrer

Research output: Contribution to journalArticlepeer-review

32 Scopus citations

Abstract

Like normal hematopoietic stem cells, leukemic stem cells depend on their bone marrow (BM) microenvironment for survival, but the underlying mechanisms remain largely unknown. We have studied the contribution of nestin+ BM mesenchymal stem cells (BMSCs) to MLL-AF9-driven acute myeloid leukemia (AML) development and chemoresistance in vivo. Unlike bulk stroma, nestin+ BMSC numbers are not reduced in AML, but their function changes to support AML cells, at the expense of non-mutated hematopoietic stem cells (HSCs). Nestin+ cell depletion delays leukemogenesis in primary AML mice and selectively decreases AML, but not normal, cells in chimeric mice. Nestin+ BMSCs support survival and chemotherapy relapse of AML through increased oxidative phosphorylation, tricarboxylic acid (TCA) cycle activity, and glutathione (GSH)-mediated antioxidant defense. Therefore, AML cells co-opt energy sources and antioxidant defense mechanisms from BMSCs to survive chemotherapy. Forte et al. reveal that nestin+ bone marrow stromal cells directly contribute to leukemogenesis and chemotherapy resistance in an in vivo model of acute myeloid leukemia. Nestin+ BMSCs support leukemic stem cells through a dual mechanism of increased bioenergetic capacity through OXPHOS and TCA and glutathione-dependent antioxidant defense.

Original languageEnglish
Pages (from-to)829-843.e9
JournalCell metabolism
Volume32
Issue number5
DOIs
StatePublished - Nov 3 2020

Keywords

  • OXPHOS
  • TCA cycle
  • acute myeloid leukemia
  • antioxidant
  • bone marrow mesenchymal stem cells
  • chemotherapy
  • glutathione
  • hematopoietic stem cell niche
  • metabolic adaptation
  • microenvironment

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