Investigating the translational and metabolic reprogramming of the bone marrow niche in myeloid malignancy

Abstract

In acute myeloid leukaemia (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 was, until now, unclear. This study 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;NPMc mutations, we show that AML protein synthesis levels increase at relapse dependently on nestin+ BMSCs. Inhibiting cap-dependent translation in BMSCs abolishes their chemoprotective ability, whereas BMSCs and their EVs rescue cap-dependent translation inhibition and survival of AML cells. Consequently, eIF4A inhibition synergises with conventional chemotherapy and treatment with BMSC-derived EVs increases AML translation and accelerates disease progression after therapy. Together, these results suggest that AML cells rely on BMSCs to maintain an oncogenic translational program required for relapse.