دورية أكاديمية
Asparagine transport through SLC1A5/ASCT2 and SLC38A5/SNAT5 is essential for BCP-ALL cell survival and a potential therapeutic target.
العنوان: | Asparagine transport through SLC1A5/ASCT2 and SLC38A5/SNAT5 is essential for BCP-ALL cell survival and a potential therapeutic target. |
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المؤلفون: | Taurino G; Laboratory of General Pathology, Department of Medicine and Surgery, University of Parma, Parma, Italy., Dander E; Tettamanti Center, Fondazione IRCCS San Gerardo Dei Tintori, Monza, Italy., Chiu M; Laboratory of General Pathology, Department of Medicine and Surgery, University of Parma, Parma, Italy., Pozzi G; Laboratory of Human Anatomy, Department of Medicine and Surgery, University of Parma, Parma, Italy., Maccari C; Laboratory of Industrial Toxicology, Department of Medicine and Surgery, University of Parma, Parma, Italy., Starace R; Tettamanti Center, Fondazione IRCCS San Gerardo Dei Tintori, Monza, Italy., Silvestri D; Tettamanti Center, Fondazione IRCCS San Gerardo Dei Tintori, Monza, Italy., Griffini E; Laboratory of General Pathology, Department of Medicine and Surgery, University of Parma, Parma, Italy., Bianchi MG; Laboratory of General Pathology, Department of Medicine and Surgery, University of Parma, Parma, Italy.; MRH-Microbiome Research Hub, Parco Area Delle Scienze 11/A, University of Parma, Parma, Italy., Carubbi C; Laboratory of Human Anatomy, Department of Medicine and Surgery, University of Parma, Parma, Italy., Andreoli R; Laboratory of Industrial Toxicology, Department of Medicine and Surgery, University of Parma, Parma, Italy.; CERT-Center of Excellence for Toxicological Research, University of Parma, Parma, Italy., Mirandola P; Laboratory of Human Anatomy, Department of Medicine and Surgery, University of Parma, Parma, Italy., Valsecchi MG; Biostatistics and Clinical Epidemiology, Fondazione IRCCS San Gerardo Dei Tintori, Monza, Italy.; School of Medicine and Surgery, University of Milano-Bicocca, Milan, Italy., Rizzari C; Department of Pediatrics, Fondazione IRCCS San Gerardo Dei Tintori, Monza, Italy., D'Amico G; Tettamanti Center, Fondazione IRCCS San Gerardo Dei Tintori, Monza, Italy., Bussolati O; Laboratory of General Pathology, Department of Medicine and Surgery, University of Parma, Parma, Italy.; MRH-Microbiome Research Hub, Parco Area Delle Scienze 11/A, University of Parma, Parma, Italy. |
المصدر: | British journal of haematology [Br J Haematol] 2024 Jul; Vol. 205 (1), pp. 175-188. Date of Electronic Publication: 2024 May 13. |
نوع المنشور: | Journal Article |
اللغة: | English |
بيانات الدورية: | Publisher: Wiley-Blackwell Country of Publication: England NLM ID: 0372544 Publication Model: Print-Electronic Cited Medium: Internet ISSN: 1365-2141 (Electronic) Linking ISSN: 00071048 NLM ISO Abbreviation: Br J Haematol Subsets: MEDLINE |
أسماء مطبوعة: | Publication: Oxford : Wiley-Blackwell Original Publication: Oxford : Blackwell Scientific Publications |
مواضيع طبية MeSH: | Amino Acid Transport System ASC*/metabolism , Amino Acid Transport System ASC*/genetics , Asparagine*/metabolism , Minor Histocompatibility Antigens*/metabolism , Minor Histocompatibility Antigens*/genetics , Precursor B-Cell Lymphoblastic Leukemia-Lymphoma*/metabolism , Precursor B-Cell Lymphoblastic Leukemia-Lymphoma*/drug therapy , Precursor B-Cell Lymphoblastic Leukemia-Lymphoma*/pathology , Precursor B-Cell Lymphoblastic Leukemia-Lymphoma*/genetics , Cell Survival*/drug effects, Humans ; Amino Acid Transport System A/metabolism ; Amino Acid Transport System A/genetics ; Cell Line, Tumor ; Asparaginase/pharmacology ; Asparaginase/therapeutic use ; Cell Proliferation/drug effects ; Child |
مستخلص: | 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. (© 2024 British Society for Haematology and John Wiley & Sons Ltd.) |
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معلومات مُعتمدة: | International Myeloma Foundation; IG 2019 Id.23354 Associazione Italiana per la Ricerca sul Cancro; 2022C5RHRT MUR-Italian Ministry of University and Research |
فهرسة مساهمة: | Keywords: L‐asparaginase; acute lymphoblastic leukaemia; asparagine; bone marrow niche; glutamine; tumour microenvironment |
المشرفين على المادة: | 0 (Amino Acid Transport System ASC) 0 (SLC1A5 protein, human) 7006-34-0 (Asparagine) 0 (Minor Histocompatibility Antigens) 0 (Amino Acid Transport System A) EC 3.5.1.1 (Asparaginase) |
تواريخ الأحداث: | Date Created: 20240513 Date Completed: 20240712 Latest Revision: 20240712 |
رمز التحديث: | 20240712 |
DOI: | 10.1111/bjh.19516 |
PMID: | 38736325 |
قاعدة البيانات: | MEDLINE |
تدمد: | 1365-2141 |
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DOI: | 10.1111/bjh.19516 |