In vivo assessment of glutamine anaplerosis into the TCA cycle in human pre-malignant and malignant clonal plasma cells

Gonsalves, Wilson I.; Jang, Jin Sung; Jessen, Erik; Hitosugi, Taro; Evans, Laura A.; Jevremović, Dragan; Pettersson, Xuan-Mai; Bush, Alexander Graham; Gransee, Jaimee; Anderson, Emilie; Kumar, Santosh; Nair, K. Sreekumaran

doi:10.1186/s40170-020-00235-4

Cited by 18 publications

(17 citation statements)

References 35 publications

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“…For instance, human multiple myeloma is Gln-auxotrophic [49][50][51][52] , and nutritional exchanges between cancer and stromal cells are highly likely, although the definition of the possible role of SNAT5 therein awaits further experimental work.…”

Section: Discussionmentioning

confidence: 99%

ALL blasts drive primary mesenchymal stromal cells to increase asparagine availability during asparaginase treatment

et al. 2021

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Mechanisms underlying the resistance of Acute Lymphoblastic Leukemia (ALL) blasts to L-asparaginase are still incompletely known. Here we demonstrate that human primary bone marrow mesenchymal stromal cells (MSCs) successfully adapt to L-asparaginase and markedly protect leukemic blasts from the enzyme-dependent cytotoxicity through an amino acid trade-off. ALL blasts synthesize and secrete glutamine, thus increasing extracellular glutamine availability for stromal cells. In turn, MSCs use glutamine, either synthesized through Glutamine Synthetase (GS) or imported, to produce asparagine, which is then extruded to sustain asparagine-auxotroph leukemic cells. GS inhibition prevents mesenchymal cells adaptation to L-asparaginase, lowers glutamine secretion by ALL blasts, and markedly hinders the protection exerted by MSCs on leukemic cells. The pro-survival amino acid exchange is hindered by the inhibition or silencing of the asparagine efflux transporter SNAT5, which is induced in mesenchymal cells by ALL blasts. Consistently, primary MSCs from ALL patients express higher levels of SNAT5 (p < 0.05), secrete more asparagine (p < 0.05), and protect leukemic blasts (p < 0.05) better than MSCs isolated from healthy donors. In conclusion, ALL blasts arrange a pro-leukemic amino acid trade-off with bone marrow mesenchymal cells, which depends on GS and SNAT5 and promotes leukemic cell survival during L-asparaginase treatment.

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Section: Discussionmentioning

confidence: 99%

ALL blasts drive primary mesenchymal stromal cells to increase asparagine availability during asparaginase treatment

et al. 2021

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“…In turn, the inhibition GLS1 that catalyzes glutamine, by benzophenanthridinone (BPI) induces MM apoptosis [186]. An increased glutamine anaplerosis toward TCA cycle is observed in malignant MM cells and this increase is even more marked in comparison with MGUS and overt myeloma [187]. Importantly and different from normal plasma cells in this regard, glycolysis and OXPHOS compensate each other as well as glycolysis and glutaminolysis [132].…”

Section: Global Alteration Of MM Metabolismmentioning

confidence: 99%

Targeting Reactive Oxygen Species Metabolism to Induce Myeloma Cell Death

Caillot

Dakik

Mazurier

et al. 2021

Cancers

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Multiple myeloma (MM) is a common hematological disease characterized by the accumulation of clonal malignant plasma cells in the bone marrow. Over the past two decades, new therapeutic strategies have significantly improved the treatment outcome and patients survival. Nevertheless, most MM patients relapse underlying the need of new therapeutic approaches. Plasma cells are prone to produce large amounts of immunoglobulins causing the production of intracellular ROS. Although adapted to high level of ROS, MM cells die when exposed to drugs increasing ROS production either directly or by inhibiting antioxidant enzymes. In this review, we discuss the efficacy of ROS-generating drugs for inducing MM cell death and counteracting acquired drug resistance specifically toward proteasome inhibitors.

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“…Metabolic changes parallel MM progression (41). For instance, glutamine-dependent anaplerosis of the TCA cycle increases from MGUS to myeloma (12). Moreover, a sizable degree of metabolic heterogeneity may be present in the same MM (42), suggesting that subpopulations of MM cells may respond in a different way to therapeutic treatments.…”

Section: F]fdg In Extramedullary Lesion Inmentioning

confidence: 99%

“…[ 18 F](2S,4R)-4-fluoroglutamine ([ 18 F]4-FGln) has been recently tested in different types of glutamine (Gln)-dependent tumors (8)(9)(10). MM is a Gln-addicted cancer that strictly relies on extracellular Gln uptake, and the use of Gln for anaplerosis has been also confirmed in patients (11,12). However, [ 18 F]4-FGln as a PET tracer in MM has not been investigated yet.…”

Section: Introductionmentioning

confidence: 99%

[18F](2S,4R)-4-Fluoroglutamine as a New Positron Emission Tomography Tracer in Myeloma

et al. 2021

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The high glycolytic activity of multiple myeloma (MM) cells is the rationale for use of Positron Emission Tomography (PET) with 18F-fluorodeoxyglucose ([18F]FDG) to detect both bone marrow (BM) and extramedullary disease. However, new tracers are actively searched because [18F]FDG-PET has some limitations and there is a portion of MM patients who are negative. Glutamine (Gln) addiction has been recently described as a typical metabolic feature of MM cells. Yet, the possible exploitation of Gln as a PET tracer in MM has never been assessed so far and is investigated in this study in preclinical models. Firstly, we have synthesized enantiopure (2S,4R)-4-fluoroglutamine (4-FGln) and validated it as a Gln transport analogue in human MM cell lines, comparing its uptake with that of 3H-labelled Gln. We then radiosynthesized [18F]4-FGln, tested its uptake in two different in vivo murine MM models, and checked the effect of Bortezomib, a proteasome inhibitor currently used in the treatment of MM. Both [18F]4-FGln and [18F]FDG clearly identified the spleen as site of MM cell colonization in C57BL/6 mice, challenged with syngeneic Vk12598 cells and assessed by PET. NOD.SCID mice, subcutaneously injected with human MM JJN3 cells, showed high values of both [18F]4-FGln and [18F]FDG uptake. Bortezomib significantly reduced the uptake of both radiopharmaceuticals in comparison with vehicle at post treatment PET. However, a reduction of glutaminolytic, but not of glycolytic, tumor volume was evident in mice showing the highest response to Bortezomib. Our data indicate that [18F](2S,4R)-4-FGln is a new PET tracer in preclinical MM models, yielding a rationale to design studies in MM patients.

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In vivo assessment of glutamine anaplerosis into the TCA cycle in human pre-malignant and malignant clonal plasma cells

Cited by 18 publications

References 35 publications

ALL blasts drive primary mesenchymal stromal cells to increase asparagine availability during asparaginase treatment

ALL blasts drive primary mesenchymal stromal cells to increase asparagine availability during asparaginase treatment

Targeting Reactive Oxygen Species Metabolism to Induce Myeloma Cell Death

[18F](2S,4R)-4-Fluoroglutamine as a New Positron Emission Tomography Tracer in Myeloma

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