A preclinical model of peripheral T‐cell lymphoma GATA3 reveals DNA damage response pathway vulnerability
Abstract Peripheral T‐cell lymphoma (PTCL) represents a rare group of heterogeneous diseases in urgent need of effective treatments. A scarcity of disease‐relevant preclinical models hinders research advances. Here, we isolated a novel mouse (m)PTCL by serially transplanting a lymphoma from a germin...
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| Format: | Article |
| Language: | English |
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Springer Nature
2022-05-01
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| Series: | EMBO Molecular Medicine |
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| Online Access: | https://doi.org/10.15252/emmm.202215816 |
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| author | Elizabeth A Kuczynski Giulia Morlino Alison Peter Anna M L Coenen‐Stass Jennifer I Moss Neha Wali Oona Delpuech Avinash Reddy Anisha Solanki Charles Sinclair Dinis P Calado Larissa S Carnevalli |
| author_facet | Elizabeth A Kuczynski Giulia Morlino Alison Peter Anna M L Coenen‐Stass Jennifer I Moss Neha Wali Oona Delpuech Avinash Reddy Anisha Solanki Charles Sinclair Dinis P Calado Larissa S Carnevalli |
| author_sort | Elizabeth A Kuczynski |
| collection | DOAJ |
| description | Abstract Peripheral T‐cell lymphoma (PTCL) represents a rare group of heterogeneous diseases in urgent need of effective treatments. A scarcity of disease‐relevant preclinical models hinders research advances. Here, we isolated a novel mouse (m)PTCL by serially transplanting a lymphoma from a germinal center B‐cell hyperplasia model (Cγ1‐Cre Blimp1fl/fl) through immune‐competent mice. Lymphoma cells were identified as clonal TCRβ+ T‐helper cells expressing T‐follicular helper markers. We also observed coincident B‐cell activation and development of a de novo B‐cell lymphoma in the model, reminiscent of B‐cell activation/lymphomagenesis found in human PTCL. Molecular profiling linked the mPTCL to the high‐risk “GATA3” subtype of PTCL, showing GATA3 and Th2 gene expression, PI3K/mTOR pathway enrichment, hyperactivated MYC, and genome instability. Exome sequencing identified a human‐relevant oncogenic β‐catenin mutation possibly involved in T‐cell lymphomagenesis. Prolonged treatment responses were achieved in vivo by targeting ATR in the DNA damage response (DDR), a result corroborated in PTCL cell lines. This work provides mechanistic insight into the molecular and immunological drivers of T‐cell lymphomagenesis and proposes DDR inhibition as an effective and readily translatable therapy in PTCL. |
| format | Article |
| id | doaj-art-38ad0878cfd84d5a8f2b9b112c61dadb |
| institution | Kabale University |
| issn | 1757-4676 1757-4684 |
| language | English |
| publishDate | 2022-05-01 |
| publisher | Springer Nature |
| record_format | Article |
| series | EMBO Molecular Medicine |
| spelling | doaj-art-38ad0878cfd84d5a8f2b9b112c61dadb2025-08-20T03:43:14ZengSpringer NatureEMBO Molecular Medicine1757-46761757-46842022-05-0114612110.15252/emmm.202215816A preclinical model of peripheral T‐cell lymphoma GATA3 reveals DNA damage response pathway vulnerabilityElizabeth A Kuczynski0Giulia Morlino1Alison Peter2Anna M L Coenen‐Stass3Jennifer I Moss4Neha Wali5Oona Delpuech6Avinash Reddy7Anisha Solanki8Charles Sinclair9Dinis P Calado10Larissa S Carnevalli11Oncology R&D, AstraZenecaImmunity & Cancer Laboratory, Francis Crick InstituteOncology R&D, AstraZenecaOncology R&D, AstraZenecaOncology R&D, AstraZenecaOncology R&D, AstraZenecaOncology R&D, AstraZenecaOncology R&D, AstraZenecaOncology R&D, AstraZenecaOncology R&D, AstraZenecaImmunity & Cancer Laboratory, Francis Crick InstituteOncology R&D, AstraZenecaAbstract Peripheral T‐cell lymphoma (PTCL) represents a rare group of heterogeneous diseases in urgent need of effective treatments. A scarcity of disease‐relevant preclinical models hinders research advances. Here, we isolated a novel mouse (m)PTCL by serially transplanting a lymphoma from a germinal center B‐cell hyperplasia model (Cγ1‐Cre Blimp1fl/fl) through immune‐competent mice. Lymphoma cells were identified as clonal TCRβ+ T‐helper cells expressing T‐follicular helper markers. We also observed coincident B‐cell activation and development of a de novo B‐cell lymphoma in the model, reminiscent of B‐cell activation/lymphomagenesis found in human PTCL. Molecular profiling linked the mPTCL to the high‐risk “GATA3” subtype of PTCL, showing GATA3 and Th2 gene expression, PI3K/mTOR pathway enrichment, hyperactivated MYC, and genome instability. Exome sequencing identified a human‐relevant oncogenic β‐catenin mutation possibly involved in T‐cell lymphomagenesis. Prolonged treatment responses were achieved in vivo by targeting ATR in the DNA damage response (DDR), a result corroborated in PTCL cell lines. This work provides mechanistic insight into the molecular and immunological drivers of T‐cell lymphomagenesis and proposes DDR inhibition as an effective and readily translatable therapy in PTCL.https://doi.org/10.15252/emmm.202215816DNA damage responseGATA3peripheral T‐cell lymphomasyngeneic mouse modelT‐follicular helper cell |
| spellingShingle | Elizabeth A Kuczynski Giulia Morlino Alison Peter Anna M L Coenen‐Stass Jennifer I Moss Neha Wali Oona Delpuech Avinash Reddy Anisha Solanki Charles Sinclair Dinis P Calado Larissa S Carnevalli A preclinical model of peripheral T‐cell lymphoma GATA3 reveals DNA damage response pathway vulnerability EMBO Molecular Medicine DNA damage response GATA3 peripheral T‐cell lymphoma syngeneic mouse model T‐follicular helper cell |
| title | A preclinical model of peripheral T‐cell lymphoma GATA3 reveals DNA damage response pathway vulnerability |
| title_full | A preclinical model of peripheral T‐cell lymphoma GATA3 reveals DNA damage response pathway vulnerability |
| title_fullStr | A preclinical model of peripheral T‐cell lymphoma GATA3 reveals DNA damage response pathway vulnerability |
| title_full_unstemmed | A preclinical model of peripheral T‐cell lymphoma GATA3 reveals DNA damage response pathway vulnerability |
| title_short | A preclinical model of peripheral T‐cell lymphoma GATA3 reveals DNA damage response pathway vulnerability |
| title_sort | preclinical model of peripheral t cell lymphoma gata3 reveals dna damage response pathway vulnerability |
| topic | DNA damage response GATA3 peripheral T‐cell lymphoma syngeneic mouse model T‐follicular helper cell |
| url | https://doi.org/10.15252/emmm.202215816 |
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