Asparagine transport through SLC1A5/ASCT2 and SLC38A5/SNAT5 is essential for BCP‐ALL cell survival and a potential therapeutic target

• Published in: British journal of haematology 2024-07, Vol.205 (1), p.175-188
• Main Authors: Taurino, Giuseppe, Dander, Erica, Chiu, Martina, Pozzi, Giulia, Maccari, Chiara, Starace, Rita, Silvestri, Daniela, Griffini, Erika, Bianchi, Massimiliano G., Carubbi, Cecilia, Andreoli, Roberta, Mirandola, Prisco, Valsecchi, Maria Grazia, Rizzari, Carmelo, D'Amico, Giovanna, Bussolati, Ovidio
• Format: Article
• Language: English
• Subjects: acute lymphoblastic leukaemia; Acute lymphoblastic leukemia; Amino Acid Transport System A - genetics; Amino Acid Transport System A - metabolism; Amino Acid Transport System ASC - genetics; Amino Acid Transport System ASC - metabolism; Asparaginase; Asparaginase - pharmacology; Asparaginase - therapeutic use; Asparagine; Asparagine - metabolism; Autophagy; bone marrow niche; Cell death; Cell Line, Tumor; Cell proliferation; Cell Proliferation - drug effects; Cell survival; Cell Survival - drug effects; Child; Cytotoxicity; glutamine; Humans; Induction therapy; L‐asparaginase; Mesenchymal stem cells; Minimal residual disease; Minor Histocompatibility Antigens - genetics; Minor Histocompatibility Antigens - metabolism; Nutrient deficiency; Pediatrics; Precursor B-Cell Lymphoblastic Leukemia-Lymphoma - drug therapy; Precursor B-Cell Lymphoblastic Leukemia-Lymphoma - genetics; Precursor B-Cell Lymphoblastic Leukemia-Lymphoma - metabolism; Precursor B-Cell Lymphoblastic Leukemia-Lymphoma - pathology; Stromal cells; Therapeutic targets; TOR protein; tumour microenvironment
• ISSN: 0007-1048; 1365-2141; 1365-2141
• DOI: 10.1111/bjh.19516

Summary 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. In the bone marrow niche of BCP acute lymphoblastic leukaemia (ALL), mesenchymal stromal cells (MSC) exploit the bidirectional transporter SNAT5 to provide the auxotrophic neoplastic blasts with Asn. SNAT5, together with ASCT2, is also used by the blasts to internalize Asn. Inhibitors of these transporters hinder the amino acid crosstalk between the two cell populations, leading to mTOR inhibition, severe nutritional stress, proliferative arrest and, eventually, cell death of leukaemic blasts.