Inhibition of Rag GTPase signaling in mice suppresses B cell responses and lymphomagenesis with minimal detrimental trade-offs
Summary: B lymphocytes are exquisitely sensitive to fluctuations in nutrient signaling by the Rag GTPases, and 15% of follicular lymphomas (FLs) harbor activating mutations in RRAGC. Hence, a potential therapeutic approach against malignant B cells is to inhibit Rag GTPase signaling, but because suc...
| Main Authors: | , , , , , , , , |
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| Format: | Article |
| Language: | English |
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Elsevier
2021-07-01
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| Series: | Cell Reports |
| Subjects: | |
| Online Access: | http://www.sciencedirect.com/science/article/pii/S2211124721007701 |
| _version_ | 1818718187663917056 |
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| author | Ana Ortega-Molina Cristina Lebrero-Fernández Alba Sanz Nerea Deleyto-Seldas Ana Belén Plata-Gómez Camino Menéndez Osvaldo Graña-Castro Eduardo Caleiras Alejo Efeyan |
| author_facet | Ana Ortega-Molina Cristina Lebrero-Fernández Alba Sanz Nerea Deleyto-Seldas Ana Belén Plata-Gómez Camino Menéndez Osvaldo Graña-Castro Eduardo Caleiras Alejo Efeyan |
| author_sort | Ana Ortega-Molina |
| collection | DOAJ |
| description | Summary: B lymphocytes are exquisitely sensitive to fluctuations in nutrient signaling by the Rag GTPases, and 15% of follicular lymphomas (FLs) harbor activating mutations in RRAGC. Hence, a potential therapeutic approach against malignant B cells is to inhibit Rag GTPase signaling, but because such inhibitors are still to be developed, efficacy and safety remain unknown. We generated knockin mice expressing a hypomorphic variant of RagC (Q119L); RagCQ119L/+ mice are viable and show attenuated nutrient signaling. B lymphocyte activation is cell-intrinsically impaired in RagCQ119L/+ mice, which also show significant suppression of genetically induced lymphomagenesis and autoimmunity. Surprisingly, no overt systemic trade-offs or phenotypic alterations caused by partial suppression of nutrient signaling are seen in other organs, and RagCQ119L/+ mice show normal longevity and normal age-dependent health decline. These results support the efficacy and safety of moderate inhibition of nutrient signaling against pathological B cells. |
| first_indexed | 2024-12-17T19:47:04Z |
| format | Article |
| id | doaj.art-694fa35b49bc4bf58162d32777298cb0 |
| institution | Directory Open Access Journal |
| issn | 2211-1247 |
| language | English |
| last_indexed | 2024-12-17T19:47:04Z |
| publishDate | 2021-07-01 |
| publisher | Elsevier |
| record_format | Article |
| series | Cell Reports |
| spelling | doaj.art-694fa35b49bc4bf58162d32777298cb02022-12-21T21:34:51ZengElsevierCell Reports2211-12472021-07-01362109372Inhibition of Rag GTPase signaling in mice suppresses B cell responses and lymphomagenesis with minimal detrimental trade-offsAna Ortega-Molina0Cristina Lebrero-Fernández1Alba Sanz2Nerea Deleyto-Seldas3Ana Belén Plata-Gómez4Camino Menéndez5Osvaldo Graña-Castro6Eduardo Caleiras7Alejo Efeyan8Metabolism and Cell Signaling Laboratory, Spanish National Cancer Research Centre (CNIO), Melchor Fernandez Almagro 3, Madrid 28029, Spain; Corresponding authorMetabolism and Cell Signaling Laboratory, Spanish National Cancer Research Centre (CNIO), Melchor Fernandez Almagro 3, Madrid 28029, SpainMetabolism and Cell Signaling Laboratory, Spanish National Cancer Research Centre (CNIO), Melchor Fernandez Almagro 3, Madrid 28029, SpainMetabolism and Cell Signaling Laboratory, Spanish National Cancer Research Centre (CNIO), Melchor Fernandez Almagro 3, Madrid 28029, SpainMetabolism and Cell Signaling Laboratory, Spanish National Cancer Research Centre (CNIO), Melchor Fernandez Almagro 3, Madrid 28029, SpainMetabolism and Cell Signaling Laboratory, Spanish National Cancer Research Centre (CNIO), Melchor Fernandez Almagro 3, Madrid 28029, SpainBioinformatics Unit, Spanish National Cancer Research Centre (CNIO), Madrid, SpainHistopathology Unit, Spanish National Cancer Research Centre (CNIO), Madrid, SpainMetabolism and Cell Signaling Laboratory, Spanish National Cancer Research Centre (CNIO), Melchor Fernandez Almagro 3, Madrid 28029, Spain; Corresponding authorSummary: B lymphocytes are exquisitely sensitive to fluctuations in nutrient signaling by the Rag GTPases, and 15% of follicular lymphomas (FLs) harbor activating mutations in RRAGC. Hence, a potential therapeutic approach against malignant B cells is to inhibit Rag GTPase signaling, but because such inhibitors are still to be developed, efficacy and safety remain unknown. We generated knockin mice expressing a hypomorphic variant of RagC (Q119L); RagCQ119L/+ mice are viable and show attenuated nutrient signaling. B lymphocyte activation is cell-intrinsically impaired in RagCQ119L/+ mice, which also show significant suppression of genetically induced lymphomagenesis and autoimmunity. Surprisingly, no overt systemic trade-offs or phenotypic alterations caused by partial suppression of nutrient signaling are seen in other organs, and RagCQ119L/+ mice show normal longevity and normal age-dependent health decline. These results support the efficacy and safety of moderate inhibition of nutrient signaling against pathological B cells.http://www.sciencedirect.com/science/article/pii/S2211124721007701B cell lymphomagerminal centerlymphocytesmTORRRAGCnutrient signaling |
| spellingShingle | Ana Ortega-Molina Cristina Lebrero-Fernández Alba Sanz Nerea Deleyto-Seldas Ana Belén Plata-Gómez Camino Menéndez Osvaldo Graña-Castro Eduardo Caleiras Alejo Efeyan Inhibition of Rag GTPase signaling in mice suppresses B cell responses and lymphomagenesis with minimal detrimental trade-offs Cell Reports B cell lymphoma germinal center lymphocytes mTOR RRAGC nutrient signaling |
| title | Inhibition of Rag GTPase signaling in mice suppresses B cell responses and lymphomagenesis with minimal detrimental trade-offs |
| title_full | Inhibition of Rag GTPase signaling in mice suppresses B cell responses and lymphomagenesis with minimal detrimental trade-offs |
| title_fullStr | Inhibition of Rag GTPase signaling in mice suppresses B cell responses and lymphomagenesis with minimal detrimental trade-offs |
| title_full_unstemmed | Inhibition of Rag GTPase signaling in mice suppresses B cell responses and lymphomagenesis with minimal detrimental trade-offs |
| title_short | Inhibition of Rag GTPase signaling in mice suppresses B cell responses and lymphomagenesis with minimal detrimental trade-offs |
| title_sort | inhibition of rag gtpase signaling in mice suppresses b cell responses and lymphomagenesis with minimal detrimental trade offs |
| topic | B cell lymphoma germinal center lymphocytes mTOR RRAGC nutrient signaling |
| url | http://www.sciencedirect.com/science/article/pii/S2211124721007701 |
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