The gene expression profile and cell of origin of canine peripheral T-cell lymphoma
Abstract Background Peripheral T-cell lymphoma (PTCL) refers to a heterogenous group of T-cell neoplasms with poor treatment responses and survival times. Canine PTCL clinically and immunophenotypically resembles the most common human subtype, PTCL-not otherwise specified (PTCL-NOS), leading to inte...
| Main Authors: | , , , , , |
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| Format: | Article |
| Language: | English |
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BMC
2024-01-01
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| Series: | BMC Cancer |
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| Online Access: | https://doi.org/10.1186/s12885-023-11762-w |
| _version_ | 1797363182138818560 |
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| author | Eileen Owens Lauren Harris Adam Harris Janna Yoshimoto Robert Burnett Anne Avery |
| author_facet | Eileen Owens Lauren Harris Adam Harris Janna Yoshimoto Robert Burnett Anne Avery |
| author_sort | Eileen Owens |
| collection | DOAJ |
| description | Abstract Background Peripheral T-cell lymphoma (PTCL) refers to a heterogenous group of T-cell neoplasms with poor treatment responses and survival times. Canine PTCL clinically and immunophenotypically resembles the most common human subtype, PTCL-not otherwise specified (PTCL-NOS), leading to interest in this canine disease as a naturally occurring model for human PTCL. Gene expression profiling in human PTCL-NOS has helped characterize this ambiguous diagnosis into distinct subtypes, but similar gene expression profiling in canine PTCL is lacking. Methods Bulk RNA-sequencing was performed on tumor samples from 33 dogs with either CD4+ (26/33), CD8+ (4/33), or CD4-CD8- (3/33) PTCL as diagnosed by flow cytometry, and sorted CD4+ and CD8+ lymphocytes from healthy control dogs. Following normalization of RNA-seq data, we performed differential gene expression and unsupervised clustering methods. Gene set enrichment analysis was performed to determine the enrichment of canine CD4+ PTCL for human PTCL-NOS, oncogenic pathways, and various stages of T-cell development gene signatures. We utilized gene set variation analysis to evaluate individual canine CD4+ PTCLs for various human and murine T-cell and thymocyte gene signatures. Cultured canine PTCL cells were treated with a pan-PI3K inhibitor, and cell survival and proliferation were compared to DMSO-treated controls. Expression of GATA3 and phosphorylated AKT was validated by immunohistochemistry. Results While the canine CD4+ PTCL phenotype exhibited a consistent gene expression profile, the expression profiles of CD8+ and CD4-CD8- canine PTCLs were more heterogeneous. Canine CD4+ PTCL had increased expression of GATA3, upregulation of its target genes, enrichment for PI3K/AKT/mTOR signaling, and downregulation of PTEN, features consistent with the more aggressive GATA3-PTCL subtype of human PTCL-NOS. In vitro assays validated the reliance of canine CD4+ PTCL cells on PI3K/AKT/mTOR signaling for survival and proliferation. Canine CD4+ PTCL was enriched for thymic precursor gene signatures, exhibited increased expression of markers of immaturity (CD34, KIT, DNTT, and CCR9), and downregulated genes associated with the T-cell receptor, MHC class II associated genes (DLA-DQA1, DLA-DRA, HLA-DQB1, and HLA-DQB2), and CD25. Conclusions Canine CD4+ PTCL most closely resembled the GATA3-PTCL subtype of PTCL-NOS and may originate from an earlier stage of T-cell development than the more conventionally posited mature T-helper cell origin. |
| first_indexed | 2024-03-08T16:17:24Z |
| format | Article |
| id | doaj.art-7ca445c6ace2430e96df83db8c213020 |
| institution | Directory Open Access Journal |
| issn | 1471-2407 |
| language | English |
| last_indexed | 2024-03-08T16:17:24Z |
| publishDate | 2024-01-01 |
| publisher | BMC |
| record_format | Article |
| series | BMC Cancer |
| spelling | doaj.art-7ca445c6ace2430e96df83db8c2130202024-01-07T12:30:17ZengBMCBMC Cancer1471-24072024-01-0124111910.1186/s12885-023-11762-wThe gene expression profile and cell of origin of canine peripheral T-cell lymphomaEileen Owens0Lauren Harris1Adam Harris2Janna Yoshimoto3Robert Burnett4Anne Avery5Department of Microbiology, Immunology & Pathology; College of Veterinary Medicine and Biomedical Sciences, Colorado State University (EO, LH, AH, JY, RB, AA)Department of Microbiology, Immunology & Pathology; College of Veterinary Medicine and Biomedical Sciences, Colorado State University (EO, LH, AH, JY, RB, AA)Department of Microbiology, Immunology & Pathology; College of Veterinary Medicine and Biomedical Sciences, Colorado State University (EO, LH, AH, JY, RB, AA)Department of Microbiology, Immunology & Pathology; College of Veterinary Medicine and Biomedical Sciences, Colorado State University (EO, LH, AH, JY, RB, AA)Department of Microbiology, Immunology & Pathology; College of Veterinary Medicine and Biomedical Sciences, Colorado State University (EO, LH, AH, JY, RB, AA)Department of Microbiology, Immunology & Pathology; College of Veterinary Medicine and Biomedical Sciences, Colorado State University (EO, LH, AH, JY, RB, AA)Abstract Background Peripheral T-cell lymphoma (PTCL) refers to a heterogenous group of T-cell neoplasms with poor treatment responses and survival times. Canine PTCL clinically and immunophenotypically resembles the most common human subtype, PTCL-not otherwise specified (PTCL-NOS), leading to interest in this canine disease as a naturally occurring model for human PTCL. Gene expression profiling in human PTCL-NOS has helped characterize this ambiguous diagnosis into distinct subtypes, but similar gene expression profiling in canine PTCL is lacking. Methods Bulk RNA-sequencing was performed on tumor samples from 33 dogs with either CD4+ (26/33), CD8+ (4/33), or CD4-CD8- (3/33) PTCL as diagnosed by flow cytometry, and sorted CD4+ and CD8+ lymphocytes from healthy control dogs. Following normalization of RNA-seq data, we performed differential gene expression and unsupervised clustering methods. Gene set enrichment analysis was performed to determine the enrichment of canine CD4+ PTCL for human PTCL-NOS, oncogenic pathways, and various stages of T-cell development gene signatures. We utilized gene set variation analysis to evaluate individual canine CD4+ PTCLs for various human and murine T-cell and thymocyte gene signatures. Cultured canine PTCL cells were treated with a pan-PI3K inhibitor, and cell survival and proliferation were compared to DMSO-treated controls. Expression of GATA3 and phosphorylated AKT was validated by immunohistochemistry. Results While the canine CD4+ PTCL phenotype exhibited a consistent gene expression profile, the expression profiles of CD8+ and CD4-CD8- canine PTCLs were more heterogeneous. Canine CD4+ PTCL had increased expression of GATA3, upregulation of its target genes, enrichment for PI3K/AKT/mTOR signaling, and downregulation of PTEN, features consistent with the more aggressive GATA3-PTCL subtype of human PTCL-NOS. In vitro assays validated the reliance of canine CD4+ PTCL cells on PI3K/AKT/mTOR signaling for survival and proliferation. Canine CD4+ PTCL was enriched for thymic precursor gene signatures, exhibited increased expression of markers of immaturity (CD34, KIT, DNTT, and CCR9), and downregulated genes associated with the T-cell receptor, MHC class II associated genes (DLA-DQA1, DLA-DRA, HLA-DQB1, and HLA-DQB2), and CD25. Conclusions Canine CD4+ PTCL most closely resembled the GATA3-PTCL subtype of PTCL-NOS and may originate from an earlier stage of T-cell development than the more conventionally posited mature T-helper cell origin.https://doi.org/10.1186/s12885-023-11762-wLymphomaT-cellCancerGene expressionTranscriptomicsRNA-seq |
| spellingShingle | Eileen Owens Lauren Harris Adam Harris Janna Yoshimoto Robert Burnett Anne Avery The gene expression profile and cell of origin of canine peripheral T-cell lymphoma BMC Cancer Lymphoma T-cell Cancer Gene expression Transcriptomics RNA-seq |
| title | The gene expression profile and cell of origin of canine peripheral T-cell lymphoma |
| title_full | The gene expression profile and cell of origin of canine peripheral T-cell lymphoma |
| title_fullStr | The gene expression profile and cell of origin of canine peripheral T-cell lymphoma |
| title_full_unstemmed | The gene expression profile and cell of origin of canine peripheral T-cell lymphoma |
| title_short | The gene expression profile and cell of origin of canine peripheral T-cell lymphoma |
| title_sort | gene expression profile and cell of origin of canine peripheral t cell lymphoma |
| topic | Lymphoma T-cell Cancer Gene expression Transcriptomics RNA-seq |
| url | https://doi.org/10.1186/s12885-023-11762-w |
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