Abstract / Summary
Abstract Background Bortezomib resistance remains a major barrier to durable responses in multiple myeloma, but how metabolic adaptation within the bone marrow niche sustains this phenotype remains incompletely understood. Methods We integrated metabolomic profiling, isotope tracing, bulk RNA sequencing, single-cell RNA sequencing, co-culture tracing, molecular perturbation assays, protein–metabolite binding analyses, and pharmacological screening to investigate the role of SLC45A4-mediated putrescine uptake in bortezomib resistance. Results Bortezomib-resistant myeloma cells preferentially accumulated putrescine through enhanced uptake rather than de novo polyamine biosynthesis. SLC45A4 was upregulated in resistant CD138⁺ myeloma cells and promoted putrescine import and bortezomib resistance. Mechanistically, SLC45A4-mediated putrescine accumulation was accompanied by increased HOXA1 recovery in putrescine-associated fractions and enhanced HOXA1-associated NF-κB signaling. Single-cell and co-culture tracing analyses further suggested that MDSCs in the bone marrow niche serve as a source of putrescine acquired by myeloma cells. Pharmacological suppression of this axis by abiraterone acetate, alone or combined with the HOX/PBX inhibitor HXR9, attenuated the resistance-associated phenotype. Conclusions These findings identify an MDSC-supported SLC45A4–putrescine–HOXA1–NF-κB axis as a metabolic mechanism contributing to bortezomib resistance in multiple myeloma and nominate niche-dependent metabolic crosstalk as a potential therapeutic vulnerability.