Dependence on glutamine uptake and glutamine addiction characterize myeloma cells: A new attractive target

Marina Bolzoni, M. Chiu, Fabrizio Accardi, Rosanna Vescovini, Irma Airoldi, Paola Storti, Katia Todoerti, Luca Agnelli, Gabriele Missale, R. Andreoli, Massimiliano G. Bianchi, Manfredi Allegri, Amelia Barilli, F. Nicolini, Albertina Cavalli, Federica Costa, Valentina Marchica, D. Toscani, Cristina Mancini, Eugenia MartellaValeria Dall'Asta, G. Donofrio, Franco Aversa, Ovidio Bussolati, Nicola Giuliani

Research output: Contribution to journalArticle

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 languageEnglish
Pages (from-to)667-679
Number of pages13
JournalBlood
Volume128
Issue number5
DOIs
Publication statusPublished - 2016

Fingerprint

Glutamine
Multiple Myeloma
Cell Line
Glutamate-Ammonia Ligase
Cell growth
Ammonium Compounds
Glutamic Acid
Bone
Growth
Cells
Glutaminase
Asparaginase
Paraproteinemias
Transcriptome
Metabolism
Gene expression
Bone Marrow Cells
Therapeutics
Down-Regulation
Bone Marrow

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 journalArticle

Bolzoni, M, Chiu, M, Accardi, F, Vescovini, R, Airoldi, I, Storti, P, Todoerti, K, Agnelli, L, Missale, G, Andreoli, R, Bianchi, MG, Allegri, M, Barilli, A, Nicolini, F, Cavalli, A, Costa, F, Marchica, V, Toscani, D, Mancini, C, Martella, E, Dall'Asta, V, Donofrio, G, Aversa, F, Bussolati, O & Giuliani, N 2016, 'Dependence on glutamine uptake and glutamine addiction characterize myeloma cells: A new attractive target', Blood, vol. 128, no. 5, pp. 667-679. https://doi.org/10.1182/blood-2016-01-690743
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. / Dependence on glutamine uptake and glutamine addiction characterize myeloma cells : A new attractive target. In: Blood. 2016 ; Vol. 128, No. 5. pp. 667-679.
@article{9ce1c5392e984e8fac78ec06f440ff88,
title = "Dependence on glutamine uptake and glutamine addiction characterize myeloma cells: A new attractive target",
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.",
author = "Marina Bolzoni and M. Chiu and Fabrizio Accardi and Rosanna Vescovini and Irma Airoldi and Paola Storti and Katia Todoerti and Luca Agnelli and Gabriele Missale and R. Andreoli and Bianchi, {Massimiliano G.} and Manfredi Allegri and Amelia Barilli and F. Nicolini and Albertina Cavalli and Federica Costa and Valentina Marchica and D. Toscani and Cristina Mancini and Eugenia Martella and Valeria Dall'Asta and G. Donofrio and Franco Aversa and Ovidio Bussolati and Nicola Giuliani",
year = "2016",
doi = "10.1182/blood-2016-01-690743",
language = "English",
volume = "128",
pages = "667--679",
journal = "Blood",
issn = "0006-4971",
publisher = "American Society of Hematology",
number = "5",

}

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.

UR - http://www.scopus.com/inward/record.url?scp=84994667572&partnerID=8YFLogxK

UR - http://www.scopus.com/inward/citedby.url?scp=84994667572&partnerID=8YFLogxK

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 -