Abstract
The importance of glutamine (Gln) metabolism in multiple myeloma (MM) cells and its potential role as a therapeutic target are still unknown, although it has been reported that human myeloma cell lines (HMCLs) are highly sensitiveto Gln depletion. In this study, we found that both HMCLs and primary bone marrow (BM) CD138+ cells produced large amounts of ammonium in the presence of Gln. MM patients have lower BM plasma Gln with higher ammonium and glutamate than patients with indolent monoclonal gam-mopathies. Interestingly, HMCLs expressed glutaminase (GLS1) and were sensitivetoits inhibition, whereas they exhibited negligible expression of glutamine synthetase (GS). High GLS1 and low GS expression were also observed in primary CD138+ cells. Gln-free incubation or treatment with the glutaminolytic enzyme L-asparaginase depleted the cell contents of Gln, glutamate, and the anaplerotic substrate 2-oxoglutarate, inhibiting MM cell growth. Consistent with the dependence of MM cells on extracellular Gln, a gene expression profile analysis, on both proprietary and published datasets, showed an increased expression of the Gln transporters SNAT1, ASCT2, and LAT1 by CD138+ cells across the progression of monoclonal gammopathies. Among these transporters, only ASCT2 inhibition in HMCLs caused a marked decrease in Gln uptake and a significant fall in cell growth. Consistently, stable ASCT2 down regulation by alentiviral approach inhibited HMCL growth inv itro and in a murine model. In conclusion, M Mcells strictly depend on extracellular Gln and show features of Gln addiction. Therefore, the inhibition of Gln uptake is a new attractive therapeutic strategy for MM.
| Original language | English |
|---|---|
| Pages (from-to) | 667-679 |
| Number of pages | 13 |
| Journal | Blood |
| Volume | 128 |
| Issue number | 5 |
| DOIs | |
| Publication status | Published - 2016 |
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ASJC Scopus subject areas
- Immunology
- Biochemistry
- Hematology
- Cell Biology
Cite this
Dependence on glutamine uptake and glutamine addiction characterize myeloma cells : A new attractive target. / Bolzoni, Marina; Chiu, M.; Accardi, Fabrizio; Vescovini, Rosanna; Airoldi, Irma; Storti, Paola; Todoerti, Katia; Agnelli, Luca; Missale, Gabriele; Andreoli, R.; Bianchi, Massimiliano G.; Allegri, Manfredi; Barilli, Amelia; Nicolini, F.; Cavalli, Albertina; Costa, Federica; Marchica, Valentina; Toscani, D.; Mancini, Cristina; Martella, Eugenia; Dall'Asta, Valeria; Donofrio, G.; Aversa, Franco; Bussolati, Ovidio; Giuliani, Nicola.
In: Blood, Vol. 128, No. 5, 2016, p. 667-679.Research output: Contribution to journal › Article
}
TY - JOUR
T1 - Dependence on glutamine uptake and glutamine addiction characterize myeloma cells
T2 - A new attractive target
AU - Bolzoni, Marina
AU - Chiu, M.
AU - Accardi, Fabrizio
AU - Vescovini, Rosanna
AU - Airoldi, Irma
AU - Storti, Paola
AU - Todoerti, Katia
AU - Agnelli, Luca
AU - Missale, Gabriele
AU - Andreoli, R.
AU - Bianchi, Massimiliano G.
AU - Allegri, Manfredi
AU - Barilli, Amelia
AU - Nicolini, F.
AU - Cavalli, Albertina
AU - Costa, Federica
AU - Marchica, Valentina
AU - Toscani, D.
AU - Mancini, Cristina
AU - Martella, Eugenia
AU - Dall'Asta, Valeria
AU - Donofrio, G.
AU - Aversa, Franco
AU - Bussolati, Ovidio
AU - Giuliani, Nicola
PY - 2016
Y1 - 2016
N2 - The importance of glutamine (Gln) metabolism in multiple myeloma (MM) cells and its potential role as a therapeutic target are still unknown, although it has been reported that human myeloma cell lines (HMCLs) are highly sensitiveto Gln depletion. In this study, we found that both HMCLs and primary bone marrow (BM) CD138+ cells produced large amounts of ammonium in the presence of Gln. MM patients have lower BM plasma Gln with higher ammonium and glutamate than patients with indolent monoclonal gam-mopathies. Interestingly, HMCLs expressed glutaminase (GLS1) and were sensitivetoits inhibition, whereas they exhibited negligible expression of glutamine synthetase (GS). High GLS1 and low GS expression were also observed in primary CD138+ cells. Gln-free incubation or treatment with the glutaminolytic enzyme L-asparaginase depleted the cell contents of Gln, glutamate, and the anaplerotic substrate 2-oxoglutarate, inhibiting MM cell growth. Consistent with the dependence of MM cells on extracellular Gln, a gene expression profile analysis, on both proprietary and published datasets, showed an increased expression of the Gln transporters SNAT1, ASCT2, and LAT1 by CD138+ cells across the progression of monoclonal gammopathies. Among these transporters, only ASCT2 inhibition in HMCLs caused a marked decrease in Gln uptake and a significant fall in cell growth. Consistently, stable ASCT2 down regulation by alentiviral approach inhibited HMCL growth inv itro and in a murine model. In conclusion, M Mcells strictly depend on extracellular Gln and show features of Gln addiction. Therefore, the inhibition of Gln uptake is a new attractive therapeutic strategy for MM.
AB - The importance of glutamine (Gln) metabolism in multiple myeloma (MM) cells and its potential role as a therapeutic target are still unknown, although it has been reported that human myeloma cell lines (HMCLs) are highly sensitiveto Gln depletion. In this study, we found that both HMCLs and primary bone marrow (BM) CD138+ cells produced large amounts of ammonium in the presence of Gln. MM patients have lower BM plasma Gln with higher ammonium and glutamate than patients with indolent monoclonal gam-mopathies. Interestingly, HMCLs expressed glutaminase (GLS1) and were sensitivetoits inhibition, whereas they exhibited negligible expression of glutamine synthetase (GS). High GLS1 and low GS expression were also observed in primary CD138+ cells. Gln-free incubation or treatment with the glutaminolytic enzyme L-asparaginase depleted the cell contents of Gln, glutamate, and the anaplerotic substrate 2-oxoglutarate, inhibiting MM cell growth. Consistent with the dependence of MM cells on extracellular Gln, a gene expression profile analysis, on both proprietary and published datasets, showed an increased expression of the Gln transporters SNAT1, ASCT2, and LAT1 by CD138+ cells across the progression of monoclonal gammopathies. Among these transporters, only ASCT2 inhibition in HMCLs caused a marked decrease in Gln uptake and a significant fall in cell growth. Consistently, stable ASCT2 down regulation by alentiviral approach inhibited HMCL growth inv itro and in a murine model. In conclusion, M Mcells strictly depend on extracellular Gln and show features of Gln addiction. Therefore, the inhibition of Gln uptake is a new attractive therapeutic strategy for MM.
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U2 - 10.1182/blood-2016-01-690743
DO - 10.1182/blood-2016-01-690743
M3 - Article
VL - 128
SP - 667
EP - 679
JO - Blood
JF - Blood
SN - 0006-4971
IS - 5
ER -