Bone marrow mesenchymal stromal cells support translation in refractory acute myeloid leukemia
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.
Authors
- Marta Serafini (ORCID: https://orcid.org/0000-0001-8105-6476)
- Simón Méndez‐Ferrer (ORCID: https://orcid.org/0000-0002-9805-9988)
- Livia E. Lisi-Vega (ORCID: https://orcid.org/0000-0001-7664-5356)
- Dorian Forte (ORCID: https://orcid.org/0000-0002-8443-605X)
- Tim Williams (ORCID: https://orcid.org/0000-0002-9775-8285)
- María García‐Fernández (ORCID: https://orcid.org/0000-0002-6436-1361)
- Alice Pievani
Institutions
- University of Cambridge (GB)
- Istituti di Ricovero e Cura a Carattere Scientifico (IT)
Publication Details
- Journal
- Cell Reports
- Published
- 2024-12-28
- DOI
- https://doi.org/10.1016/j.celrep.2024.115151
- Citations
- 13
- Primary Topic
- Acute Myeloid Leukemia Research
- Type
- article
- Field-Weighted Citation Impact
- 5.91
Funders
- Leukemia and Lymphoma Society
- MPN Research Foundation
- Baylor University
- Universität Basel
- European Hematology Association
- NHS Blood and Transplant
- Japan Agency for Medical Research and Development
- Wellcome Trust
- UK Research and Innovation
- Ministerio de Ciencia, Innovación y Universidades
- Cancer Research UK
- National Institute for Health and Care Research
- Associazione Italiana per la Ricerca sul Cancro
- Centro Nacional de Investigaciones Cardiovasculares
- Blood Cancer UK
- Horizon 2020 Framework Programme
- Medical Research Council
- Cambridge Institute for Medical Research, University of Cambridge
- HORIZON EUROPE Marie Sklodowska-Curie Actions