2. Academic Validation
  3. Bone marrow mesenchymal stromal cells support translation in refractory acute myeloid leukemia

Bone marrow mesenchymal stromal cells support translation in refractory acute myeloid leukemia

  • Cell Rep. 2025 Jan 28;44(1):115151. doi: 10.1016/j.celrep.2024.115151.
Livia E Lisi-Vega 1,  Alice Pievani 2,  María García-Fernández 1,  Dorian Forte 1,  Tim L Williams 3,  Marta Serafini 4,  Simón Méndez-Ferrer 5
Affiliations

Affiliations

  • 1 Cambridge Stem Cell Institute, Cambridge CB2 0AW, UK; Department of Haematology, University of Cambridge, Cambridge CB2 0AW, UK; National Health Service Blood and Transplant, Cambridge CB2 0AW, UK.
  • 2 Tettamanti Center, Fondazione IRCCS San Gerardo Dei Tintori, 20900 Monza, Italy.
  • 3 Department of Veterinary Medicine, University of Cambridge, Cambridge CB3 0ES, UK.
  • 4 Tettamanti Center, Fondazione IRCCS San Gerardo Dei Tintori, 20900 Monza, Italy; School of Medicine and Surgery, University of Milano-Bicocca, 20900 Monza, Italy.
  • 5 Cambridge Stem Cell Institute, Cambridge CB2 0AW, UK; Department of Haematology, University of Cambridge, Cambridge CB2 0AW, UK; National Health Service Blood and Transplant, Cambridge CB2 0AW, UK; Instituto de Biomedicina de Sevilla-IBiS (Hospitales Universitarios Virgen Del Rocío y Macarena/CSIC/Universidad de Sevilla), 41013 Seville, Spain; Departamento de Fisiología Médica y Biofísica, Universidad de Sevilla, 41009 Seville, Spain. Electronic address: sm2116@cam.ac.uk.
PMID: 39932190 DOI: 10.1016/j.celrep.2024.115151
Abstract

In acute myeloid leukemia (AML), malignant cells surviving chemotherapy rely on high mRNA translation and their microenvironmental metabolic support to drive relapse. However, the role of translational reprogramming in the niche is unclear. Here, we found that relapsing AML cells increase translation in their bone marrow (BM) niches, where BM mesenchymal stromal cells (BMSCs) become a source of eIF4A-cap-dependent translation machinery that is transferred to AML cells via extracellular vesicles (EVs) to meet their translational demands. In two independent models of highly chemo-resistant AML driven by MLL-AF9 or FLT3-ITD (internal tandem duplication) and nucleophosmin (NPMc) mutations, protein synthesis levels increase in refractory AML dependent on nestin+ BMSCs. Inhibiting cap-dependent translation in BMSCs abolishes their chemoprotective ability, while EVs from BMSCs carrying eIF4A boost AML cell translation and survival. Consequently, eIF4A inhibition synergizes with conventional chemotherapy. Together, these results suggest that AML cells rely on BMSCs to maintain an oncogenic translational program required for relapse.

Keywords

CP: Cancer; acute myeloid leukemia; bone marrow mesenchymal stromal cells; chemotherapy; extracellular vesicles; microenvironment; niche; protein synthesis; refractory; relapse; translation.

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