Alpha 2.0
Login Register
» Articles » PMID: 31209181

Glutaminase Activity of L-Asparaginase Contributes to Durable Preclinical Activity Against Acute Lymphoblastic Leukemia

Overview
Journal Mol Cancer Ther
Date 2019 Jun 19
PMID 31209181
Citations 41
Authors
Wai-Kin Chan
Thomas D Horvath
Lin Tan
Todd Link
Karine G Harutyunyan
Michael A Pontikos
Andriy Anishkin
Di Du
Leona A Martin
Eric Yin
Susan B Rempe
Sergei Sukharev
Marina Konopleva
John N Weinstein
Philip L Lorenzi
Affiliations
Soon will be listed here.
Abstract

We and others have reported that the anticancer activity of L-asparaginase (ASNase) against asparagine synthetase (ASNS)-positive cell types requires ASNase glutaminase activity, whereas anticancer activity against ASNS-negative cell types does not. Here, we attempted to disentangle the relationship between asparagine metabolism, glutamine metabolism, and downstream pathways that modulate cell viability by testing the hypothesis that ASNase anticancer activity is based on asparagine depletion rather than glutamine depletion per se. We tested ASNase wild-type (ASNase) and its glutaminase-deficient Q59L mutant (ASNase) and found that ASNase glutaminase activity contributed to durable anticancer activity against xenografts of the ASNS-negative Sup-B15 leukemia cell line in NOD/SCID gamma mice, whereas asparaginase activity alone yielded a mere growth delay. Our findings suggest that ASNase glutaminase activity is necessary for durable, single-agent anticancer activity , even against ASNS-negative cancer types.

Citing Articles

A metabolic synthetic lethality of phosphoinositide 3-kinase-driven cancer.

Andrieu G, Simonin M, Cabannes-Hamy A, Lengline E, Marcais A, Theron A Nat Commun. 2025; 16(1):2191.

PMID: 40038309 PMC: 11880427. DOI: 10.1038/s41467-025-57225-7.

Amino Acid Metabolism-Related Gene Kynureninase (KYNU) as a Prognostic Predictor and Regulator of Diffuse Large B-Cell Lymphoma.

Zhang Y, Feng S, Lv L, Wang C, Kong R, Zhong G Biochem Genet. 2025; .

PMID: 39932613 DOI: 10.1007/s10528-025-11047-w.

Acute Myeloid Leukaemia and Acute Lymphoblastic Leukaemia Classification and Metabolic Characteristics for Informing and Advancing Treatment.

Wemyss C, Jones E, Stentz R, Carding S Cancers (Basel). 2025; 16(24.

PMID: 39766036 PMC: 11675077. DOI: 10.3390/cancers16244136.

NEK8 promotes the progression of gastric cancer by reprogramming asparagine metabolism.

Wang M, Yu K, Meng F, Wang H, Li Y Mol Med. 2025; 31(1):3.

PMID: 39762761 PMC: 11702068. DOI: 10.1186/s10020-024-01062-9.

Clinical research framework proposal for ketogenic metabolic therapy in glioblastoma.

Duraj T, Kalamian M, Zuccoli G, Maroon J, DAgostino D, Scheck A BMC Med. 2024; 22(1):578.

PMID: 39639257 PMC: 11622503. DOI: 10.1186/s12916-024-03775-4.

References
1.
Szymanska B, Wilczynska-Kalak U, Kang M, Liem N, Carol H, Boehm I . Pharmacokinetic modeling of an induction regimen for in vivo combined testing of novel drugs against pediatric acute lymphoblastic leukemia xenografts. PLoS One. 2012; 7(3):e33894. PMC: 3315513. DOI: 10.1371/journal.pone.0033894. View
2.
Wu M, ARIMURA G, YUNIS A . Mechanism of sensitivity of cultured pancreatic carcinoma to asparaginase. Int J Cancer. 1978; 22(6):728-33. DOI: 10.1002/ijc.2910220615. View
3.
Tong W, Pieters R, Hop W, Lanvers-Kaminsky C, Boos J, van der Sluis I . No evidence of increased asparagine levels in the bone marrow of patients with acute lymphoblastic leukemia during asparaginase therapy. Pediatr Blood Cancer. 2012; 60(2):258-61. DOI: 10.1002/pbc.24292. View
4.
Iwamoto S, Mihara K, Downing J, Pui C, Campana D . Mesenchymal cells regulate the response of acute lymphoblastic leukemia cells to asparaginase. J Clin Invest. 2007; 117(4):1049-57. PMC: 1821067. DOI: 10.1172/JCI30235. View
5.
Chan W, Lorenzi P, Anishkin A, Purwaha P, Rogers D, Sukharev S . The glutaminase activity of L-asparaginase is not required for anticancer activity against ASNS-negative cells. Blood. 2014; 123(23):3596-606. PMC: 4047499. DOI: 10.1182/blood-2013-10-535112. View