Myeloma Cells Deplete Bone Marrow Glutamine and Inhibit Osteoblast Differentiation Limiting Asparagine Availability
Open accessAbstract
Multiple myeloma (MM) cells consume huge amounts of glutamine and, as a consequence, the amino acid concentration is lower-than-normal in the bone marrow (BM) of MM patients. Here we show that MM-dependent glutamine depletion induces glutamine synthetase in stromal cells, as demonstrated in BM biopsies of MM patients, and reproduced in vitro by co-culturing human mesenchymal stromal cells (MSCs) with MM cells. Moreover, glutamine depletion hinders osteoblast differentiation of MSCs, which is also severely blunted by the spent, low-glutamine medium of MM cells, and rescued by glutamine restitution. Glutaminase and the concentrative glutamine transporter SNAT2 are induced during osteoblastogenesis in vivo and in vitro, and both needed for MSCs differentiation, pointing to enhanced the requirement for the amino acid. Osteoblastogenesis also triggers the induction of glutamine-dependent asparagine synthetase (ASNS), and, among non-essential amino acids, asparagine rescues differentiation of glutamine-starved MSCs, by restoring the transcriptional profiles of differentiating MSCs altered by glutamine starvation. Thus, reduced asparagine availability provides a mechanistic link between MM-dependent Gln depletion in BM and impairment of osteoblast differentiation. Inhibition of Gln metabolism in MM cells and supplementation of asparagine to stromal cells may, therefore, constitute novel approaches to prevent osteolytic lesions in MM.
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Changes in metabolite availability in the multiple myeloma microenvironment produce modifications in the energy metabolism of bone cells, which in turn affect their development and function.
“Given this, it is not unexpected that changes in the metabolite availability in the MM microenvironment produce modifications in the energy metabolism of bone cells, which in turn affect their development and function [46, 47].”
From Mesenchymal stromal cells in bone marrow niche of patients with multiple myeloma: a double-edged sword (2025) · cites this paper as [46]
The Introduction and Discussion report that myeloma cells deplete bone-marrow glutamine and that glutamine shortage impairs the differentiation of mesenchymal stromal cells into osteoblasts. The paper identifies reduced asparagine availability as the link; it does not show that a change in energy metabolism mediates the effect, or establish the claim for bone cells generally. (LLM, conf=0.84)
Experimental — accuracy not yet measuredGlutamine is transported into cells through plasma-membrane glutamine transporters, specifically SLC1A5 (ASCT2), SLC7A7, and SLC38A2 (SNAT2).
“Gln is transported into the cells through plasma-membrane Gln transporters, specifically SLC1A5 (ASCT2), SLC7A7, and SLC38A2 (SNAT2) [46, 62].”
From Mesenchymal stromal cells in bone marrow niche of patients with multiple myeloma: a double-edged sword (2025) · cites this paper as [46]
Section 2.3 (page unavailable) identifies SLC1A5 as encoding the glutamine transporter ASCT2 and SLC38A2 as encoding SNAT2. It does not identify SLC7A7 as a glutamine transporter, so the full three-transporter list is not supported by this source. (LLM, conf=0.88)
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- Authors
- Chiu, M., Toscani, D., Marchica, V., Taurino, G., Costa, F., Bianchi, M. G., Andreoli, R., Franceschi, V., Storti, P., Burroughs-Garcia, J., Eufemiese, R. A., Dalla Palma, B., Campanini, N., Martella, E., Mancini, C., Shan, J., Kilberg, M. S., D’Amico, G., Dander, E., Agnelli, L., Pruneri, G., Donofrio, G., Bussolati, O., & Giuliani, N.
- Affiliations
- University of Parma (IT)
- Department of Medicine and Surgery, University of Parma, 43126 Parma, Italy
- University of Florida Health (US)
- University of Milano-Bicocca (IT)
- Fondazione IRCCS Istituto Nazionale dei Tumori (IT)
- Department of Medical-Veterinary Science, University of Parma, 43121 Parma, Italy
- Corresponding author
- Bussolati, Ovidio
- Giuliani, Nicola
- ORCID
- Venue
- Cancers
- Publisher
- MDPI AG
- Published
- 2020-11-05
- Volume
- 12
- Issue
- 11
- Pages
- 3267
- ISSN
- 2072-6694 (ISSN-L)
- PMC
- PMC7694402
- OpenAlex
- W3096462526
- Cited by
- 42
- References
- 37
- Citations by year
- 2026: 6 · 2025: 7 · 2024: 5 · 2023: 10 · 2022: 9 · 2021: 5
- FWCI
- 3.79
- Type
- journal article
- Language
- en
- Open access
- gold
- doi.org
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- Cancers (publishedVersion, cc-by)
- PubMed Central (publishedVersion, cc-by)
- PubMed (publishedVersion)
- DOAJ (DOAJ: Directory of Open Access Journals) (submittedVersion)
- Funders
- Associazione Italiana per la Ricerca sul Cancro (20299, 23354, 19272)
- International Myeloma Foundation (2018 Brian D. Novis Senior Research Grant)
- National Institutes of Health (CA203565)
- Topics
- Health Sciences › Medicine › Hematology › Multiple Myeloma Research and Treatments
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Biochemistry › Amino Acid Enzymes and Metabolism
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › Bone Metabolism and Diseases
- Keywords
- multiple myeloma, glutamine deprivation, mesenchymal stem cells, osteogenic differentiation, asparagine, asparagine synthetase, glutamine synthetase, glutamine metabolism, osteolytic lesions, amino acid metabolism
About these checks
Registry, retraction, Cites and statistics results are computed, not judged, with one exception: a printed reference that no index lists is read once by a model before it counts as a citation error. Claims are extracted by a model and kept only when their quote appears verbatim in the text; each cited source is then checked, with a model’s help, for whether it says what the claim relies on. Those verdicts can be wrong — read the claim’s quote and the cited source before relying on one.
Statistics and arithmetic are recomputed, not judged.
Confidence bands are shown only for fields calibrated on our annotated test set. None is calibrated yet, so no band is shown.
What counts as a claim ›How we measure confidence ›How we check this ›
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