Transcriptomic clustering of chronic lymphocytic leukemia: molecular subtypes based on Bruton’s tyrosine kinase expression levels
Abstract Historically, CLL prognostication relied on disease burden, reflected in clinical stage. Later, chromosome abnormalities and genomics suggested several CLL subtypes which were aligned with response to therapy. Gene expression profiling data identified pathways associated with CLL progressio...
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| Format: | Article |
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Nature Publishing Group
2024-12-01
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| Series: | Blood Cancer Journal |
| Online Access: | https://doi.org/10.1038/s41408-024-01196-3 |
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| author | Gorkem Kismali Ganiraju Manyam Nitin Jain Cristina Ivan Betty Lamothe Mary L. Ayres LaKesla R. Iles William G. Wierda Varsha Gandhi |
| author_facet | Gorkem Kismali Ganiraju Manyam Nitin Jain Cristina Ivan Betty Lamothe Mary L. Ayres LaKesla R. Iles William G. Wierda Varsha Gandhi |
| author_sort | Gorkem Kismali |
| collection | DOAJ |
| description | Abstract Historically, CLL prognostication relied on disease burden, reflected in clinical stage. Later, chromosome abnormalities and genomics suggested several CLL subtypes which were aligned with response to therapy. Gene expression profiling data identified pathways associated with CLL progression. We hypothesized that transcriptome and proteome may identify functional omics associated with CLL nosology. As a test cohort, we utilized publicly available treatment-naïve CLL transcriptomics data (n = 130) and did consensus clustering that identified BTK-expression-based clusters. The BTK-High and BTK-Low clusters were validated in public and our in-house databases (n = >550 CLL patients). To associate with functional relevance, we took samples from 151 previously treated patient with CLL and analyzed them using RNA sequencing and reverse-phase protein array. Transcript levels were strongly correlated with BTK protein levels. BTK-High subtype showed increased CCL3/CCL4 levels and disease burden such as high WBC. BTK-Low subtype showed down-regulated mRNA/proteins of DNA-repair pathway and increased DNA-damage-response, which may have contributed to enrichment of inflammatory pathway. BTK-Low subtype was rich in proapoptotic gene and protein expression and relied less on BCR pathway. High-BTK subgroup was enriched in replication/repair pathway and transcription machinery. In conclusion, profiling of 5 datasets of ~700 patients revealed unique BTK-associated expression clusters in CLL. |
| format | Article |
| id | doaj-art-07af12fd7a614f578d4eea9a3ed4fd62 |
| institution | Kabale University |
| issn | 2044-5385 |
| language | English |
| publishDate | 2024-12-01 |
| publisher | Nature Publishing Group |
| record_format | Article |
| series | Blood Cancer Journal |
| spelling | doaj-art-07af12fd7a614f578d4eea9a3ed4fd622024-12-22T12:16:09ZengNature Publishing GroupBlood Cancer Journal2044-53852024-12-0114111310.1038/s41408-024-01196-3Transcriptomic clustering of chronic lymphocytic leukemia: molecular subtypes based on Bruton’s tyrosine kinase expression levelsGorkem Kismali0Ganiraju Manyam1Nitin Jain2Cristina Ivan3Betty Lamothe4Mary L. Ayres5LaKesla R. Iles6William G. Wierda7Varsha Gandhi8Department of Experimental Therapeutics, The University of Texas MD Anderson Cancer CenterDepartment of Bioinformatics & Computational Biology, The University of Texas MD Anderson Cancer CenterDepartment of Leukemia, The University of Texas MD Anderson Cancer CenterDepartment of Experimental Therapeutics, The University of Texas MD Anderson Cancer CenterDepartment of Experimental Therapeutics, The University of Texas MD Anderson Cancer CenterDepartment of Experimental Therapeutics, The University of Texas MD Anderson Cancer CenterDepartment of Experimental Therapeutics, The University of Texas MD Anderson Cancer CenterDepartment of Leukemia, The University of Texas MD Anderson Cancer CenterDepartment of Experimental Therapeutics, The University of Texas MD Anderson Cancer CenterAbstract Historically, CLL prognostication relied on disease burden, reflected in clinical stage. Later, chromosome abnormalities and genomics suggested several CLL subtypes which were aligned with response to therapy. Gene expression profiling data identified pathways associated with CLL progression. We hypothesized that transcriptome and proteome may identify functional omics associated with CLL nosology. As a test cohort, we utilized publicly available treatment-naïve CLL transcriptomics data (n = 130) and did consensus clustering that identified BTK-expression-based clusters. The BTK-High and BTK-Low clusters were validated in public and our in-house databases (n = >550 CLL patients). To associate with functional relevance, we took samples from 151 previously treated patient with CLL and analyzed them using RNA sequencing and reverse-phase protein array. Transcript levels were strongly correlated with BTK protein levels. BTK-High subtype showed increased CCL3/CCL4 levels and disease burden such as high WBC. BTK-Low subtype showed down-regulated mRNA/proteins of DNA-repair pathway and increased DNA-damage-response, which may have contributed to enrichment of inflammatory pathway. BTK-Low subtype was rich in proapoptotic gene and protein expression and relied less on BCR pathway. High-BTK subgroup was enriched in replication/repair pathway and transcription machinery. In conclusion, profiling of 5 datasets of ~700 patients revealed unique BTK-associated expression clusters in CLL.https://doi.org/10.1038/s41408-024-01196-3 |
| spellingShingle | Gorkem Kismali Ganiraju Manyam Nitin Jain Cristina Ivan Betty Lamothe Mary L. Ayres LaKesla R. Iles William G. Wierda Varsha Gandhi Transcriptomic clustering of chronic lymphocytic leukemia: molecular subtypes based on Bruton’s tyrosine kinase expression levels Blood Cancer Journal |
| title | Transcriptomic clustering of chronic lymphocytic leukemia: molecular subtypes based on Bruton’s tyrosine kinase expression levels |
| title_full | Transcriptomic clustering of chronic lymphocytic leukemia: molecular subtypes based on Bruton’s tyrosine kinase expression levels |
| title_fullStr | Transcriptomic clustering of chronic lymphocytic leukemia: molecular subtypes based on Bruton’s tyrosine kinase expression levels |
| title_full_unstemmed | Transcriptomic clustering of chronic lymphocytic leukemia: molecular subtypes based on Bruton’s tyrosine kinase expression levels |
| title_short | Transcriptomic clustering of chronic lymphocytic leukemia: molecular subtypes based on Bruton’s tyrosine kinase expression levels |
| title_sort | transcriptomic clustering of chronic lymphocytic leukemia molecular subtypes based on bruton s tyrosine kinase expression levels |
| url | https://doi.org/10.1038/s41408-024-01196-3 |
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