Hypomethylation and expression of <it>BEX2, IGSF4 </it>and <it>TIMP3 </it>indicative of <it>MLL </it>translocations in Acute Myeloid Leukemia
<p>Abstract</p> <p>Background</p> <p>Translocations of the <it>Mixed Lineage Leukemia </it>(<it>MLL</it>) gene occur in a subset (5%) of acute myeloid leukemias (AML), and in mixed phenotype acute leukemias in infancy - a disease with extremely p...
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| Format: | Article |
| Language: | English |
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BMC
2009-10-01
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| Series: | Molecular Cancer |
| Online Access: | http://www.molecular-cancer.com/content/8/1/86 |
| _version_ | 1818334871134666752 |
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| author | Slany Robert Scherr Michaela Marschalek Rolf Meyer Claus Dirks Wilhelm G Röhrs Sonja Wallace Andrew Drexler Hans G Quentmeier Hilmar |
| author_facet | Slany Robert Scherr Michaela Marschalek Rolf Meyer Claus Dirks Wilhelm G Röhrs Sonja Wallace Andrew Drexler Hans G Quentmeier Hilmar |
| author_sort | Slany Robert |
| collection | DOAJ |
| description | <p>Abstract</p> <p>Background</p> <p>Translocations of the <it>Mixed Lineage Leukemia </it>(<it>MLL</it>) gene occur in a subset (5%) of acute myeloid leukemias (AML), and in mixed phenotype acute leukemias in infancy - a disease with extremely poor prognosis. Animal model systems show that <it>MLL </it>gain of function mutations may contribute to leukemogenesis. Wild-type (wt) <it>MLL </it>possesses histone methyltransferase activity and functions at the level of chromatin organization by affecting the expression of specific target genes. While numerous MLL fusion proteins exert a diverse array of functions, they ultimately serve to induce transcription of specific genes. Hence, acute lymphoblastic leukemias (ALL) with <it>MLL </it>mutations (<it>MLL</it>mu) exhibit characteristic gene expression profiles including high-level expression of <it>HOXA </it>cluster genes. Here, we aimed to relate <it>MLL </it>mutational status and tumor suppressor gene (TSG) methylation/expression in acute leukemia cell lines.</p> <p>Results</p> <p>Using MS-MLPA (methylation-specific multiplex ligation-dependent probe amplification assay), methylation of 24 different TSG was analyzed in 28 <it>MLL</it>mu and <it>MLL</it>wt acute leukemia cell lines. On average, 1.8/24 TSG were methylated in <it>MLL</it>mu AML cells, while 6.2/24 TSG were methylated in <it>MLL</it>wt AML cells. Hypomethylation and expression of the TSG <it>BEX2, IGSF4 </it>and <it>TIMP3 </it>turned out to be characteristic of <it>MLL</it>mu AML cell lines. <it>MLL</it>wt AML cell lines displayed hypermethylated TSG promoters resulting in transcriptional silencing. Demethylating agents and inhibitors of histone deacetylases restored expression of <it>BEX2, IGSF4 </it>and <it>TIMP3</it>, confirming epigenetic silencing of these genes in <it>MLL</it>wt cells. The positive correlation between <it>MLL </it>translocation, TSG hypomethylation and expression suggested that <it>MLL </it>fusion proteins were responsible for dysregulation of TSG expression in <it>MLL</it>mu cells. This concept was supported by our observation that <it>Bex2 </it>mRNA levels in <it>MLL-ENL </it>transgenic mouse cell lines required expression of the <it>MLL </it>fusion gene.</p> <p>Conclusion</p> <p>These results suggest that the conspicuous expression of the TSG <it>BEX2, IGSF4 </it>and <it>TIMP3 </it>in <it>MLL</it>mu AML cell lines is the consequence of altered epigenetic properties of <it>MLL </it>fusion proteins.</p> |
| first_indexed | 2024-12-13T14:14:25Z |
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| institution | Directory Open Access Journal |
| issn | 1476-4598 |
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| publishDate | 2009-10-01 |
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| series | Molecular Cancer |
| spelling | doaj.art-c097646eb03647afae03ee3bf6ba2d8b2022-12-21T23:42:21ZengBMCMolecular Cancer1476-45982009-10-01818610.1186/1476-4598-8-86Hypomethylation and expression of <it>BEX2, IGSF4 </it>and <it>TIMP3 </it>indicative of <it>MLL </it>translocations in Acute Myeloid LeukemiaSlany RobertScherr MichaelaMarschalek RolfMeyer ClausDirks Wilhelm GRöhrs SonjaWallace AndrewDrexler Hans GQuentmeier Hilmar<p>Abstract</p> <p>Background</p> <p>Translocations of the <it>Mixed Lineage Leukemia </it>(<it>MLL</it>) gene occur in a subset (5%) of acute myeloid leukemias (AML), and in mixed phenotype acute leukemias in infancy - a disease with extremely poor prognosis. Animal model systems show that <it>MLL </it>gain of function mutations may contribute to leukemogenesis. Wild-type (wt) <it>MLL </it>possesses histone methyltransferase activity and functions at the level of chromatin organization by affecting the expression of specific target genes. While numerous MLL fusion proteins exert a diverse array of functions, they ultimately serve to induce transcription of specific genes. Hence, acute lymphoblastic leukemias (ALL) with <it>MLL </it>mutations (<it>MLL</it>mu) exhibit characteristic gene expression profiles including high-level expression of <it>HOXA </it>cluster genes. Here, we aimed to relate <it>MLL </it>mutational status and tumor suppressor gene (TSG) methylation/expression in acute leukemia cell lines.</p> <p>Results</p> <p>Using MS-MLPA (methylation-specific multiplex ligation-dependent probe amplification assay), methylation of 24 different TSG was analyzed in 28 <it>MLL</it>mu and <it>MLL</it>wt acute leukemia cell lines. On average, 1.8/24 TSG were methylated in <it>MLL</it>mu AML cells, while 6.2/24 TSG were methylated in <it>MLL</it>wt AML cells. Hypomethylation and expression of the TSG <it>BEX2, IGSF4 </it>and <it>TIMP3 </it>turned out to be characteristic of <it>MLL</it>mu AML cell lines. <it>MLL</it>wt AML cell lines displayed hypermethylated TSG promoters resulting in transcriptional silencing. Demethylating agents and inhibitors of histone deacetylases restored expression of <it>BEX2, IGSF4 </it>and <it>TIMP3</it>, confirming epigenetic silencing of these genes in <it>MLL</it>wt cells. The positive correlation between <it>MLL </it>translocation, TSG hypomethylation and expression suggested that <it>MLL </it>fusion proteins were responsible for dysregulation of TSG expression in <it>MLL</it>mu cells. This concept was supported by our observation that <it>Bex2 </it>mRNA levels in <it>MLL-ENL </it>transgenic mouse cell lines required expression of the <it>MLL </it>fusion gene.</p> <p>Conclusion</p> <p>These results suggest that the conspicuous expression of the TSG <it>BEX2, IGSF4 </it>and <it>TIMP3 </it>in <it>MLL</it>mu AML cell lines is the consequence of altered epigenetic properties of <it>MLL </it>fusion proteins.</p>http://www.molecular-cancer.com/content/8/1/86 |
| spellingShingle | Slany Robert Scherr Michaela Marschalek Rolf Meyer Claus Dirks Wilhelm G Röhrs Sonja Wallace Andrew Drexler Hans G Quentmeier Hilmar Hypomethylation and expression of <it>BEX2, IGSF4 </it>and <it>TIMP3 </it>indicative of <it>MLL </it>translocations in Acute Myeloid Leukemia Molecular Cancer |
| title | Hypomethylation and expression of <it>BEX2, IGSF4 </it>and <it>TIMP3 </it>indicative of <it>MLL </it>translocations in Acute Myeloid Leukemia |
| title_full | Hypomethylation and expression of <it>BEX2, IGSF4 </it>and <it>TIMP3 </it>indicative of <it>MLL </it>translocations in Acute Myeloid Leukemia |
| title_fullStr | Hypomethylation and expression of <it>BEX2, IGSF4 </it>and <it>TIMP3 </it>indicative of <it>MLL </it>translocations in Acute Myeloid Leukemia |
| title_full_unstemmed | Hypomethylation and expression of <it>BEX2, IGSF4 </it>and <it>TIMP3 </it>indicative of <it>MLL </it>translocations in Acute Myeloid Leukemia |
| title_short | Hypomethylation and expression of <it>BEX2, IGSF4 </it>and <it>TIMP3 </it>indicative of <it>MLL </it>translocations in Acute Myeloid Leukemia |
| title_sort | hypomethylation and expression of it bex2 igsf4 it and it timp3 it indicative of it mll it translocations in acute myeloid leukemia |
| url | http://www.molecular-cancer.com/content/8/1/86 |
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