Differential Transcriptional Reprogramming by Wild Type and Lymphoma-Associated Mutant MYC Proteins as B-Cells Convert to a Lymphoma Phenotype
The MYC transcription factor regulates a vast number of genes and is implicated in many human malignancies. In some hematological malignancies, MYC is frequently subject to missense mutations that enhance its transformation activity. Here, we use a novel murine cell system to (i) characterize the tr...
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MDPI AG
2021-12-01
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| Series: | Cancers |
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| Online Access: | https://www.mdpi.com/2072-6694/13/23/6093 |
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| author | Amir Mahani Gustav Arvidsson Laia Sadeghi Alf Grandien Anthony P. H. Wright |
| author_facet | Amir Mahani Gustav Arvidsson Laia Sadeghi Alf Grandien Anthony P. H. Wright |
| author_sort | Amir Mahani |
| collection | DOAJ |
| description | The MYC transcription factor regulates a vast number of genes and is implicated in many human malignancies. In some hematological malignancies, MYC is frequently subject to missense mutations that enhance its transformation activity. Here, we use a novel murine cell system to (i) characterize the transcriptional effects of progressively increasing MYC levels as normal primary B-cells transform to lymphoma cells and (ii) determine how this gene regulation program is modified by lymphoma-associated MYC mutations (T58A and T58I) that enhance its transformation activity. Unlike many previous studies, the cell system exploits primary B-cells that are transduced to allow regulated MYC expression under circumstances where apoptosis and senescence pathways are abrogated by the over-expression of the Bcl-xL and BMI1 proteins. In such cells, transition from a normal to a lymphoma phenotype is directly dependent on the MYC expression level, without a requirement for secondary events that are normally required during MYC-driven oncogenic transformation. A generalized linear model approach allowed an integrated analysis of RNA sequencing data to identify regulated genes in relation to both progressively increasing MYC level and wild type or mutant status. Using this design, a total of 7569 regulated genes were identified, of which the majority (<i>n</i> = 7263) were regulated in response to progressively increased levels of wild type MYC, while a smaller number of genes (<i>n</i> = 917) were differentially regulated, compared to wild type MYC, in T58A MYC- and/or T58I MYC-expressing cells. Unlike most genes that are similarly regulated by both wild type and mutant MYC genes, the set of 917 genes did not significantly overlap with known lipopolysaccharide regulated genes, which represent genes regulated by MYC in normal B cells. The genes that were differently regulated in cells expressing mutant MYC proteins were significantly enriched in DNA replication and G2 phase to mitosis transition genes. Thus, mutants affecting MYC proteins may augment quantitative oncogenic effects on the expression of normal MYC-target genes with qualitative oncogenic effects, by which sets of cell cycle genes are abnormally targeted by MYC as B cells transition into lymphoma cells. The T58A and T58I mutations augment MYC-driven transformation by distinct mechanisms. |
| first_indexed | 2024-03-10T04:55:35Z |
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| institution | Directory Open Access Journal |
| issn | 2072-6694 |
| language | English |
| last_indexed | 2024-03-10T04:55:35Z |
| publishDate | 2021-12-01 |
| publisher | MDPI AG |
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| series | Cancers |
| spelling | doaj.art-b91652bbcd524fb3a9fc7a321badadd02023-11-23T02:14:32ZengMDPI AGCancers2072-66942021-12-011323609310.3390/cancers13236093Differential Transcriptional Reprogramming by Wild Type and Lymphoma-Associated Mutant MYC Proteins as B-Cells Convert to a Lymphoma PhenotypeAmir Mahani0Gustav Arvidsson1Laia Sadeghi2Alf Grandien3Anthony P. H. Wright4Division for Biomolecular and Cellular Medicine, Department of Laboratory Medicine, Karolinska Institutet, 17177 Stockholm, SwedenDivision for Biomolecular and Cellular Medicine, Department of Laboratory Medicine, Karolinska Institutet, 17177 Stockholm, SwedenDivision for Biomolecular and Cellular Medicine, Department of Laboratory Medicine, Karolinska Institutet, 17177 Stockholm, SwedenCenter for Hematology and Regenerative Medicine, Department of Medicine, Karolinska Institutet, 17177 Stockholm, SwedenDivision for Biomolecular and Cellular Medicine, Department of Laboratory Medicine, Karolinska Institutet, 17177 Stockholm, SwedenThe MYC transcription factor regulates a vast number of genes and is implicated in many human malignancies. In some hematological malignancies, MYC is frequently subject to missense mutations that enhance its transformation activity. Here, we use a novel murine cell system to (i) characterize the transcriptional effects of progressively increasing MYC levels as normal primary B-cells transform to lymphoma cells and (ii) determine how this gene regulation program is modified by lymphoma-associated MYC mutations (T58A and T58I) that enhance its transformation activity. Unlike many previous studies, the cell system exploits primary B-cells that are transduced to allow regulated MYC expression under circumstances where apoptosis and senescence pathways are abrogated by the over-expression of the Bcl-xL and BMI1 proteins. In such cells, transition from a normal to a lymphoma phenotype is directly dependent on the MYC expression level, without a requirement for secondary events that are normally required during MYC-driven oncogenic transformation. A generalized linear model approach allowed an integrated analysis of RNA sequencing data to identify regulated genes in relation to both progressively increasing MYC level and wild type or mutant status. Using this design, a total of 7569 regulated genes were identified, of which the majority (<i>n</i> = 7263) were regulated in response to progressively increased levels of wild type MYC, while a smaller number of genes (<i>n</i> = 917) were differentially regulated, compared to wild type MYC, in T58A MYC- and/or T58I MYC-expressing cells. Unlike most genes that are similarly regulated by both wild type and mutant MYC genes, the set of 917 genes did not significantly overlap with known lipopolysaccharide regulated genes, which represent genes regulated by MYC in normal B cells. The genes that were differently regulated in cells expressing mutant MYC proteins were significantly enriched in DNA replication and G2 phase to mitosis transition genes. Thus, mutants affecting MYC proteins may augment quantitative oncogenic effects on the expression of normal MYC-target genes with qualitative oncogenic effects, by which sets of cell cycle genes are abnormally targeted by MYC as B cells transition into lymphoma cells. The T58A and T58I mutations augment MYC-driven transformation by distinct mechanisms.https://www.mdpi.com/2072-6694/13/23/6093MYCMYC mutants (T58A and T58I)lymphomaoncogene deregulationcell cycleribosome biogenesis |
| spellingShingle | Amir Mahani Gustav Arvidsson Laia Sadeghi Alf Grandien Anthony P. H. Wright Differential Transcriptional Reprogramming by Wild Type and Lymphoma-Associated Mutant MYC Proteins as B-Cells Convert to a Lymphoma Phenotype Cancers MYC MYC mutants (T58A and T58I) lymphoma oncogene deregulation cell cycle ribosome biogenesis |
| title | Differential Transcriptional Reprogramming by Wild Type and Lymphoma-Associated Mutant MYC Proteins as B-Cells Convert to a Lymphoma Phenotype |
| title_full | Differential Transcriptional Reprogramming by Wild Type and Lymphoma-Associated Mutant MYC Proteins as B-Cells Convert to a Lymphoma Phenotype |
| title_fullStr | Differential Transcriptional Reprogramming by Wild Type and Lymphoma-Associated Mutant MYC Proteins as B-Cells Convert to a Lymphoma Phenotype |
| title_full_unstemmed | Differential Transcriptional Reprogramming by Wild Type and Lymphoma-Associated Mutant MYC Proteins as B-Cells Convert to a Lymphoma Phenotype |
| title_short | Differential Transcriptional Reprogramming by Wild Type and Lymphoma-Associated Mutant MYC Proteins as B-Cells Convert to a Lymphoma Phenotype |
| title_sort | differential transcriptional reprogramming by wild type and lymphoma associated mutant myc proteins as b cells convert to a lymphoma phenotype |
| topic | MYC MYC mutants (T58A and T58I) lymphoma oncogene deregulation cell cycle ribosome biogenesis |
| url | https://www.mdpi.com/2072-6694/13/23/6093 |
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