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B-cell precursor acute lymphoblastic leukaemia (BCP-ALL) blasts strictly depend on the transport of extra-cellular asparagine (Asn), yielding a rationale for L-asparaginase (ASNase) therapy. However, the carriers used by ALL blasts for Asn transport have not been identified yet. Exploiting RS4;11 cells as BCP-ALL model, we have found that cell Asn is lowered by either silencing or inhibition of the transporters ASCT2 or SNAT5. The inhibitors V-9302 (for ASCT2) and GluγHA (for SNAT5) markedly lower cell proliferation and, when used together, suppress mTOR activity, induce autophagy and cause a severe nutritional stress, leading to a proliferative arrest and a massive cell death in both the ASNase-sensitive RS4;11 cells and the relatively ASNase-insensitive NALM-6 cells. The cytotoxic effect is not prevented by coculturing leukaemic cells with primary mesenchymal stromal cells. Leukaemic blasts of paediatric ALL patients express ASCT2 and SNAT5 at diagnosis and undergo marked cytotoxicity when exposed to the inhibitors. ASCT2 expression is positively correlated with the minimal residual disease at the end of the induction therapy. In conclusion, ASCT2 and SNAT5 are the carriers exploited by ALL cells to transport Asn, and ASCT2 expression is associated with a lower therapeutic response. ASCT2 may thus represent a novel therapeutic target in BCP-ALL.

Titel:	Asparagine transport through SLC1A5/ASCT2 and SLC38A5/SNAT5 is essential for BCP-ALL cell survival and a potential therapeutic target.
Autor/in / Beteiligte Person:	Taurino, G ; Dander, E ; Chiu, M ; Pozzi, G ; Maccari, C ; Starace, R ; Silvestri, D ; Griffini, E ; Bianchi, MG ; Carubbi, C ; Andreoli, R ; Mirandola, P ; Valsecchi, MG ; Rizzari, C ; D'Amico, G ; Bussolati, O
Zeitschrift:	British journal of haematology, 2024-05-13
Veröffentlichung:	Ahead of Print, 2024
Medientyp:	academicJournal
ISSN:	1365-2141 (electronic)
DOI:	10.1111/bjh.19516
Sonstiges:	Nachgewiesen in: MEDLINE Sprachen: English Publication Type: Journal Article Language: English [Br J Haematol] 2024 May 13. <i>Date of Electronic Publication: </i>2024 May 13. References: Darvishi F, Jahanafrooz Z, Mokhtarzadeh A. Microbial L‐asparaginase as a promising enzyme for treatment of various cancers. Appl Microbiol Biotechnol. 2022;106(17):5335–5347. ; Maese L, Rau RE. Current use of Asparaginase in acute lymphoblastic leukemia/lymphoblastic lymphoma. Front Pediatr. 2022;10:902117. ; Chiu M, Taurino G, Bianchi MG, Kilberg MS, Bussolati O. Asparagine Synthetase in cancer: beyond acute lymphoblastic leukemia. Front Oncol. 2020;9:1480. ; Chen SH. Asparaginase therapy in pediatric acute lymphoblastic leukemia: a focus on the mode of drug resistance. Pediatr Neonatol. 2015;56(5):287–293. ; Appel IM, den Boer ML, Meijerink JPP, Veerman AJP, Reniers NCM, Pieters R. 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Asparagine transport through SLC1A5/ASCT2 and SLC38A5/SNAT5 is essential for BCP-ALL cell survival and a potential therapeutic target.