Contributions
Abstract: PB2326
Type: Publication Only
Background
Over-expression of MYC and RUNX family members collaborates strongly to drive lymphoma development, through their ability to neutralize their fail-safe methods of growth arrest and apoptosis. Although transgenic Runx2 and Myc can independently collaborate with mutational loss of p53 to induce T-cell lymphomas, their oncogenic cooperation overcomes the need to lose p53 function.
Aims
To further investigate the potent oncogenic collaboration of Runx2 and Myc and its mechanisms of neutralizing pressure for mutational loss of the p53 pathway in vivo.
Methods
This oncogene collaboration has been studied further through gene expression array analysis of premalignant thymic tissue from a Runx2/Myc transgenic mouse model (GIM). Gene expression in 10 day old pre-lymphomatous Runx2/Myc thymus was examined compared to normal age-matched controls.
Results
The transcriptome of Runx2/Myc thymus shows predominantly gene up-regulation, and the most significantly altered genes are enriched for Myc and Runx binding motifs in the promoter proximal and enhancer regions respectively, suggesting indirect co-regulation of key target genes. Notably, screening of known post-translational modifiers of p53 function reveals that the most significantly up-regulated gene is Smyd2. A role for SMYD2, a lysine methyltransferase, was further supported by its ability to block RUNX-induced senescence in primary fibroblasts. Runx2/Myc lymphoma lines lacking p53 are resistant to a potent SMYD2 inhibitor (BAY-598) but our findings do not exclude an essential role for SMYD2 in vivo.
Conclusion
We have previously observed potent collaboration of Runx2 and Myc in lymphoma development, and their ability to bypass the need for genetic loss of the p53 pathway. To better understand this collaboration, we employed a gene expression microarray approach. This study showed a predominance of up-regulated genes in the Runx2/Myc (GIM) mice compared to controls. Analysis of a panel of established p53 modifiers showed up-regulation of several genes, including Smyd2 and Prmt5. A role for SMYD2, a lysine methyltransferase, was further supported by its ability to block RUNX-induced senescence in primary fibroblasts. Runx2/Myc lymphoma lines lacking p53 are resistant to a potent SMYD2 inhibitor (BAY-598) but our findings do not exclude an essential role for SMYD2 in vivo.
Session topic: 19. Non-Hodgkin lymphoma Biology & Translational Research
Keyword(s): lymphoma, Methylation, MYC, P53
Abstract: PB2326
Type: Publication Only
Background
Over-expression of MYC and RUNX family members collaborates strongly to drive lymphoma development, through their ability to neutralize their fail-safe methods of growth arrest and apoptosis. Although transgenic Runx2 and Myc can independently collaborate with mutational loss of p53 to induce T-cell lymphomas, their oncogenic cooperation overcomes the need to lose p53 function.
Aims
To further investigate the potent oncogenic collaboration of Runx2 and Myc and its mechanisms of neutralizing pressure for mutational loss of the p53 pathway in vivo.
Methods
This oncogene collaboration has been studied further through gene expression array analysis of premalignant thymic tissue from a Runx2/Myc transgenic mouse model (GIM). Gene expression in 10 day old pre-lymphomatous Runx2/Myc thymus was examined compared to normal age-matched controls.
Results
The transcriptome of Runx2/Myc thymus shows predominantly gene up-regulation, and the most significantly altered genes are enriched for Myc and Runx binding motifs in the promoter proximal and enhancer regions respectively, suggesting indirect co-regulation of key target genes. Notably, screening of known post-translational modifiers of p53 function reveals that the most significantly up-regulated gene is Smyd2. A role for SMYD2, a lysine methyltransferase, was further supported by its ability to block RUNX-induced senescence in primary fibroblasts. Runx2/Myc lymphoma lines lacking p53 are resistant to a potent SMYD2 inhibitor (BAY-598) but our findings do not exclude an essential role for SMYD2 in vivo.
Conclusion
We have previously observed potent collaboration of Runx2 and Myc in lymphoma development, and their ability to bypass the need for genetic loss of the p53 pathway. To better understand this collaboration, we employed a gene expression microarray approach. This study showed a predominance of up-regulated genes in the Runx2/Myc (GIM) mice compared to controls. Analysis of a panel of established p53 modifiers showed up-regulation of several genes, including Smyd2 and Prmt5. A role for SMYD2, a lysine methyltransferase, was further supported by its ability to block RUNX-induced senescence in primary fibroblasts. Runx2/Myc lymphoma lines lacking p53 are resistant to a potent SMYD2 inhibitor (BAY-598) but our findings do not exclude an essential role for SMYD2 in vivo.
Session topic: 19. Non-Hodgkin lymphoma Biology & Translational Research
Keyword(s): lymphoma, Methylation, MYC, P53