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Chiu M, Toscani D, Marchica V, et al. Myeloma Cells Deplete Bone Marrow Glutamine and Inhibit Osteoblast Differentiation Limiting Asparagine Availability. Cancers (Basel). 2020;12(11)doi: 10.3390/cancers12113267.
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. (2020). Myeloma Cells Deplete Bone Marrow Glutamine and Inhibit Osteoblast Differentiation Limiting Asparagine Availability. Cancers, 12(11), . https://doi.org/10.3390/cancers12113267
Chiu, Martina, et al. "Myeloma Cells Deplete Bone Marrow Glutamine and Inhibit Osteoblast Differentiation Limiting Asparagine Availability." Cancers vol. 12,11 (2020). doi: https://doi.org/10.3390/cancers12113267
Chiu M, Toscani D, Marchica V, Taurino G, Costa F, Bianchi MG, Andreoli R, Franceschi V, Storti P, Burroughs-Garcia J, Eufemiese RA, Dalla Palma B, Campanini N, Martella E, Mancini C, Shan J, Kilberg MS, D'Amico G, Dander E, Agnelli L, Pruneri G, Donofrio G, Bussolati O, Giuliani N. Myeloma Cells Deplete Bone Marrow Glutamine and Inhibit Osteoblast Differentiation Limiting Asparagine Availability. Cancers (Basel). 2020 Nov 05;12(11). doi: 10.3390/cancers12113267. PMID: 33167336; PMCID: PMC7694402.
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Cancers (Basel). 2020 Nov 05;12(11). doi: 10.3390/cancers12113267.

Myeloma Cells Deplete Bone Marrow Glutamine and Inhibit Osteoblast Differentiation Limiting Asparagine Availability.

Cancers

Martina Chiu, Denise Toscani, Valentina Marchica, Giuseppe Taurino, Federica Costa, Massimiliano G Bianchi, Roberta Andreoli, Valentina Franceschi, Paola Storti, Jessica Burroughs-Garcia, Rosa Alba Eufemiese, Benedetta Dalla Palma, Nicoletta Campanini, Eugenia Martella, Cristina Mancini, Jixiu Shan, Michael S Kilberg, Giovanna D'Amico, Erica Dander, Luca Agnelli, Giancarlo Pruneri, Gaetano Donofrio, Ovidio Bussolati, Nicola Giuliani

Affiliations

  1. Department of Medicine and Surgery, University of Parma, 43126 Parma, Italy.
  2. Department of Medical-Veterinary Science, University of Parma, 43121 Parma, Italy.
  3. Hematology, Azienda Ospedaliero-Universitaria di Parma, 43126 Parma, Italy.
  4. Pathological Anatomy, "Azienda Ospedaliero-Universitaria di Parma", 43126 Parma, Italy.
  5. Department of Biochemistry and Molecular Biology, University of Florida College of Medicine, Gainesville, FL 32610, USA.
  6. Centro Ricerca Tettamanti, Pediatric Department, University of Milano-Bicocca, Fondazione MBBM, 20900 Monza, Italy.
  7. Department of Pathology-Fondazione IRCCS Istituto Nazionale dei Tumori, 20133 Milano, Italy.

PMID: 33167336 PMCID: PMC7694402 DOI: 10.3390/cancers12113267

Abstract

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.

Keywords: SNAT2; asparagine; asparagine synthetase; bone disease; glutaminase; glutamine; glutamine synthetase; multiple myeloma; osteoblast

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