Role of Glutamine Depletion in Directing Tissue-specific Nutrient Stress Responses to L-Asparaginase

Reinert, Rachel B.; Oberle, L. Morgan; Wek, Sheree A.; Bunpo, Piyawan; Wang, Xue Ping; Mileva, Izolda; Goodwin, Leslie O.; Aldrich, Carla J.; Durden, Donald L.; McNurlan, Margaret A.; Wek, Ronald C.; Anthony, Tracy G.

doi:10.1016/s0021-9258(19)84035-8

Cited by 30 publications

(8 citation statements)

References 60 publications

Supporting

Mentioning

Contrasting

Order By: Relevance

“…In MSCs, increased GS activity is required for the adaptation to L-asparaginase, as demonstrated by the marked cytotoxicity observed if GS was silenced or inhibited during the incubation with the drug. As other cell types 36,37 , mesenchymal cells exhibit a dramatic drop in intracellular Gln and Asn levels upon incubation with L-asparaginase, which triggers a nutritional stress, causing a proliferative arrest and the induction of ASNS and DDIT3, which encodes for the pro-apoptotic protein CHOP. Both DDIT3 and ASNS are targets of ATF4, the transcription factor that promotes the cell response to nutritional stress 38 .…”

Section: Discussionmentioning

confidence: 99%

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

et al. 2021

View full text Add to dashboard Cite

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.

show abstract

Section: Discussionmentioning

confidence: 99%

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

et al. 2021

View full text Add to dashboard Cite

show abstract

“…During the administration of ASNase, the alteration in the synthesis of liver proteins, induced by this imbalance, is directly related to the appearance of hepatotoxicity. 32,[35][36][37] The high levels of ammonia, responsible for hyperammonemia, in addition to nausea, vomiting and fatigue, are also responsible for the development of hepatotoxicity and neurotoxicity in patients. 34,38,39 The neurotoxic action of ASNase is still not entirely clear, but it is known that high levels of ammonia and Glu are associated with encephalopathy and apoptosis of neurons, which can lead to death.…”

Section: Discussionmentioning

confidence: 99%

Engineered asparaginase from Erwinia chrysanthemi enhances asparagine hydrolase activity and diminishes enzyme immunoreactivity ‐ a new promise to treat acute lymphoblastic leukemia

Costa

Moura

Lima

et al. 2021

J of Chemical Tech & Biotech

View full text Add to dashboard Cite

BACKGROUND: The treatment of acute lymphoblastic leukemia (ALL) uses the biopharmaceutical L-asparaginase (ASNase) as the main medication. This drug, from bacterial origin (Escherichia coli or Erwinia chrysanthemi), depletes L-asparagine (Asn) and secondarily L-glutamine (Gln -GLNase activity) from the bloodstream, leading leukemic cells to die by deprivation of Asn. The use of ASNase is limited by the high incidence of adverse effects, which collectively can specifically impair quality of life of patients. Its high toxicity caused by the product of the hydrolysis of amino acids and the formation of anti-ASNase antibodies often required treatment interruption, thus reducing the chances of cure and increasing the rates of disease relapse. RESULTS:In order to improve enzymatic activity, while reducing toxicity, we developed through directed evolution a doublemutant ASNase from Erwinia chrysanthemi (Erw_DM), which has specific activity for Asn 46% higher than the wild-type enzyme (Erw_WT). This makes it possible to reduce the amount of protein necessary for depletion of this amino acid and, consequently, the reduction of GLNase activity, considered toxic. In silico analysis showed that a lower number of epitopes was exposed, resulting in reduced recognition of the recombinant protein by antibody anti-ASNase observed in vitro assay. Furthermore, we observed the same cytotoxic profile for the MOLT-4 and REH ALL cell lines using 40% lower protein mass of Erw_DM to achieve the minimum enzyme activity required in the bloodstream during treatment.CONCLUSION: Altogether, our findings describe a potent and less immunogenic ASNase, an improvement that may alleviate treatment adverse effects developed in anti-ALL therapy.

show abstract

“…In addition, Reinert et al also show that Gln is reduced in liver and spleen after a single administration of E. coli L-ASNase, which was not observed for WoA derived L-ASNase [ 167 ]. Remarkably, a significant increase in Glu levels was observed for the WoA treated group.…”

Section: The Development Of Novel L-asnase Variantsmentioning

confidence: 99%

“…Remarkably, a significant increase in Glu levels was observed for the WoA treated group. The authors suggested that although Gln is not enzymatically cleaved by WoA , its turnover in mice is increased in response to Asn depletion, as Gln provides the NH 3 -group required to make more Asn, leading to a greater production of Glu [ 167 ]. Interestingly, this impact on Gln levels during L-ASNase treatment is not always clear in the clinic.…”

Section: The Development Of Novel L-asnase Variantsmentioning

confidence: 99%

Novel Insights on the Use of L-Asparaginase as an Efficient and Safe Anti-Cancer Therapy

Trimpont

Peeters

Visser

et al. 2022

Cancers

View full text Add to dashboard Cite

L-Asparaginase (L-ASNase) is an enzyme that hydrolyses the amino acid asparagine into aspartic acid and ammonia. Systemic administration of bacterial L-ASNase is successfully used to lower the bioavailability of this non-essential amino acid and to eradicate rapidly proliferating cancer cells with a high demand for exogenous asparagine. Currently, it is a cornerstone drug in the treatment of the most common pediatric cancer, acute lymphoblastic leukemia (ALL). Since these lymphoblasts lack the expression of asparagine synthetase (ASNS), these cells depend on the uptake of extracellular asparagine for survival. Interestingly, recent reports have illustrated that L-ASNase may also have clinical potential for the treatment of other aggressive subtypes of hematological or solid cancers. However, immunogenic and other severe adverse side effects limit optimal clinical use and often lead to treatment discontinuation. The design of optimized and novel L-ASNase formulations provides opportunities to overcome these limitations. In addition, identification of multiple L-ASNase resistance mechanisms, including ASNS promoter reactivation and desensitization, has fueled research into promising novel drug combinations to overcome chemoresistance. In this review, we discuss recent insights into L-ASNase adverse effects, resistance both in hematological and solid tumors, and how novel L-ASNase variants and drug combinations can expand its clinical applicability.

show abstract

Role of Glutamine Depletion in Directing Tissue-specific Nutrient Stress Responses to L-Asparaginase

Cited by 30 publications

References 60 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

Engineered asparaginase from Erwinia chrysanthemi enhances asparagine hydrolase activity and diminishes enzyme immunoreactivity ‐ a new promise to treat acute lymphoblastic leukemia

Novel Insights on the Use of L-Asparaginase as an Efficient and Safe Anti-Cancer Therapy

Contact Info

Product

Resources

About