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

• Published in: Cell reports (Cambridge) 2025-01, Vol.44 (1), p.115151, Article 115151
• Main Authors: Lisi-Vega, Livia E., Pievani, Alice, García-Fernández, María, Forte, Dorian, Williams, Tim L., Serafini, Marta, Méndez-Ferrer, Simón
• Format: Article
• Language: English
• Subjects: acute myeloid leukemia; bone marrow mesenchymal stromal cells; chemotherapy; CP: Cancer; extracellular vesicles; microenvironment; niche; protein synthesis; refractory; relapse; translation
• ISSN: 2211-1247; 2211-1247
• DOI: 10.1016/j.celrep.2024.115151

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. [Display omitted] •Increased translation in refractory AML cells and their niches•BMSCs are translationally reprogrammed in AML•BMSCs boost AML translation by EV-mediated transfer of translation-related proteins•BMSC-AML translational crosstalk is key for AML survival after chemotherapy Lisi-Vega et al. report that refractory AML is characterized by increased translation in leukemia cells and their niches. BM mesenchymal stromal cells (BMSCs) supply cap-dependent translation machinery to AML cells via extracellular vesicles. Targeting this mechanism with specific inhibitors reveals BMSC-AML translational crosstalk as a potential driver of AML recurrence.