MLL-AF4 upregulates 5-lipoxygenase expression in t(4;11) leukemia cells via the ALOX5 core promoter
5-Lipoxygenase (5-LO), encoded by the gene ALOX5, is implicated in several pathologies. As key enzyme in leukotriene biosynthesis, 5-LO plays a central role in inflammatory diseases, but the 5-LO pathway has also been linked to development of certain hematological and solid tumor malignancies. Of no...
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Frontiers Media S.A.
2025-01-01
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| Series: | Frontiers in Pharmacology |
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| Online Access: | https://www.frontiersin.org/articles/10.3389/fphar.2024.1520507/full |
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| author | Marius Hyprath Maximilian Molitor Ilona Schweighöfer Rolf Marschalek Dieter Steinhilber |
| author_facet | Marius Hyprath Maximilian Molitor Ilona Schweighöfer Rolf Marschalek Dieter Steinhilber |
| author_sort | Marius Hyprath |
| collection | DOAJ |
| description | 5-Lipoxygenase (5-LO), encoded by the gene ALOX5, is implicated in several pathologies. As key enzyme in leukotriene biosynthesis, 5-LO plays a central role in inflammatory diseases, but the 5-LO pathway has also been linked to development of certain hematological and solid tumor malignancies. Of note, previous studies have shown that the leukemogenic fusion protein MLL-AF4 strongly increases ALOX5 gene promoter activity. Here, we investigate the upregulation of ALOX5 gene expression by MLL-AF4. Using reporter assays, we first identified the tandem GC box within the ALOX5 promotor sequence as the main target of MLL-AF4. Subsequently, we narrowed down the domains within the MLL-AF4 protein responsible for ALOX5 promoter activation. Our findings indicate that MLL-AF4 binds to the ALOX5 promoter via its CXXC domain and that the AF9ID, pSER and CHD domains redundantly activate transcriptional elongation. Knockdown of the MLL-AF4 gene in the human B cell line SEM revealed that MLL-AF4 is an inducer of ALOX5 gene expression in leukemic cells with lymphoid properties. Finally, we found that the MLL-AF4-related protein MLL-AF9, a driver of acute myeloid leukemia, similarly acts on the ALOX5 promoter. Taken together, we show that two prominent MLL fusion proteins are ALOX5 gene inducers in cells with lymphoid features. |
| format | Article |
| id | doaj-art-8de3c61991fd4a1daf35cdd6df8c9385 |
| institution | Kabale University |
| issn | 1663-9812 |
| language | English |
| publishDate | 2025-01-01 |
| publisher | Frontiers Media S.A. |
| record_format | Article |
| series | Frontiers in Pharmacology |
| spelling | doaj-art-8de3c61991fd4a1daf35cdd6df8c93852025-01-14T06:10:44ZengFrontiers Media S.A.Frontiers in Pharmacology1663-98122025-01-011510.3389/fphar.2024.15205071520507MLL-AF4 upregulates 5-lipoxygenase expression in t(4;11) leukemia cells via the ALOX5 core promoterMarius Hyprath0Maximilian Molitor1Ilona Schweighöfer2Rolf Marschalek3Dieter Steinhilber4Institute of Pharmaceutical Chemistry, Goethe University, Frankfurt, GermanyInstitute of Pharmaceutical Chemistry, Goethe University, Frankfurt, GermanyInstitute of Pharmaceutical Chemistry, Goethe University, Frankfurt, GermanyInstitute of Pharmaceutical Biology, Goethe University, Frankfurt, GermanyInstitute of Pharmaceutical Chemistry, Goethe University, Frankfurt, Germany5-Lipoxygenase (5-LO), encoded by the gene ALOX5, is implicated in several pathologies. As key enzyme in leukotriene biosynthesis, 5-LO plays a central role in inflammatory diseases, but the 5-LO pathway has also been linked to development of certain hematological and solid tumor malignancies. Of note, previous studies have shown that the leukemogenic fusion protein MLL-AF4 strongly increases ALOX5 gene promoter activity. Here, we investigate the upregulation of ALOX5 gene expression by MLL-AF4. Using reporter assays, we first identified the tandem GC box within the ALOX5 promotor sequence as the main target of MLL-AF4. Subsequently, we narrowed down the domains within the MLL-AF4 protein responsible for ALOX5 promoter activation. Our findings indicate that MLL-AF4 binds to the ALOX5 promoter via its CXXC domain and that the AF9ID, pSER and CHD domains redundantly activate transcriptional elongation. Knockdown of the MLL-AF4 gene in the human B cell line SEM revealed that MLL-AF4 is an inducer of ALOX5 gene expression in leukemic cells with lymphoid properties. Finally, we found that the MLL-AF4-related protein MLL-AF9, a driver of acute myeloid leukemia, similarly acts on the ALOX5 promoter. Taken together, we show that two prominent MLL fusion proteins are ALOX5 gene inducers in cells with lymphoid features.https://www.frontiersin.org/articles/10.3389/fphar.2024.1520507/full5-lipoxygenaseMLLMLL-AF4leukemialeukocyteleukotriene |
| spellingShingle | Marius Hyprath Maximilian Molitor Ilona Schweighöfer Rolf Marschalek Dieter Steinhilber MLL-AF4 upregulates 5-lipoxygenase expression in t(4;11) leukemia cells via the ALOX5 core promoter Frontiers in Pharmacology 5-lipoxygenase MLL MLL-AF4 leukemia leukocyte leukotriene |
| title | MLL-AF4 upregulates 5-lipoxygenase expression in t(4;11) leukemia cells via the ALOX5 core promoter |
| title_full | MLL-AF4 upregulates 5-lipoxygenase expression in t(4;11) leukemia cells via the ALOX5 core promoter |
| title_fullStr | MLL-AF4 upregulates 5-lipoxygenase expression in t(4;11) leukemia cells via the ALOX5 core promoter |
| title_full_unstemmed | MLL-AF4 upregulates 5-lipoxygenase expression in t(4;11) leukemia cells via the ALOX5 core promoter |
| title_short | MLL-AF4 upregulates 5-lipoxygenase expression in t(4;11) leukemia cells via the ALOX5 core promoter |
| title_sort | mll af4 upregulates 5 lipoxygenase expression in t 4 11 leukemia cells via the alox5 core promoter |
| topic | 5-lipoxygenase MLL MLL-AF4 leukemia leukocyte leukotriene |
| url | https://www.frontiersin.org/articles/10.3389/fphar.2024.1520507/full |
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