ENL mutation and AML: a new model that reveals oncogenic condensate's function in leukemogenesis
Precise regulation of gene expression is essential for proper development and the maintenance of homeostasis in organisms. Studies have shown that some transcriptional regulatory proteins influence gene expression through the formation of dynamic, locally concentrated assemblies known as condensates...
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| Format: | Article |
| Language: | English |
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Wiley
2025-01-01
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| Series: | Molecular Oncology |
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| Online Access: | https://doi.org/10.1002/1878-0261.13731 |
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| author | Zhong Fan Yanan Jiang Xiaotian Zhang |
| author_facet | Zhong Fan Yanan Jiang Xiaotian Zhang |
| author_sort | Zhong Fan |
| collection | DOAJ |
| description | Precise regulation of gene expression is essential for proper development and the maintenance of homeostasis in organisms. Studies have shown that some transcriptional regulatory proteins influence gene expression through the formation of dynamic, locally concentrated assemblies known as condensates, while dysregulation of transcriptional condensates was associated with several cancers, such as Ewing sarcoma and AML [Wang Y et al. (2023) Nat Chem Biol 19, 1223–1234; Chandra B et al. (2022) Cancer Discov 12, 1152–1169]. Mutations in the histone acetylation “reader” eleven‐nineteen‐leukemia (ENL) have been shown to form discrete condensates at endogenous genomic targets, but it remains unclear how ENL mutations drive tumorigenesis and whether it is correlated with their condensate formation property. Liu et al. now show, using a conditional knock‐in mouse model, that ENL YEATS domain mutation is a bona fide oncogenic driver for AML. This mutant ENL forms condensates in hematopoietic stem/progenitor cells at the genomic loci of key leukemogenic genes, including Meis1 and Hoxa cluster genes, and disrupting condensate formation via mutagenesis impairs its chromatin and oncogenic function. Furthermore, they show that small‐molecule inhibition of the acetyl‐binding activity displaces ENL mutant condensates from oncogenic target loci, and this inhibitor significantly impairs the onset and progression of AML driven by mutant ENL in vivo. |
| format | Article |
| id | doaj-art-a871ad9c9a784326a885c0ccbc7e7006 |
| institution | Kabale University |
| issn | 1574-7891 1878-0261 |
| language | English |
| publishDate | 2025-01-01 |
| publisher | Wiley |
| record_format | Article |
| series | Molecular Oncology |
| spelling | doaj-art-a871ad9c9a784326a885c0ccbc7e70062025-01-07T14:42:32ZengWileyMolecular Oncology1574-78911878-02612025-01-0119171010.1002/1878-0261.13731ENL mutation and AML: a new model that reveals oncogenic condensate's function in leukemogenesisZhong Fan0Yanan Jiang1Xiaotian Zhang2Department of Biochemistry and Molecular Biology University of Texas Health Science Center at Houston, McGovern Medical School TX USADepartment of Biochemistry and Molecular Biology University of Texas Health Science Center at Houston, McGovern Medical School TX USADepartment of Biochemistry and Molecular Biology University of Texas Health Science Center at Houston, McGovern Medical School TX USAPrecise regulation of gene expression is essential for proper development and the maintenance of homeostasis in organisms. Studies have shown that some transcriptional regulatory proteins influence gene expression through the formation of dynamic, locally concentrated assemblies known as condensates, while dysregulation of transcriptional condensates was associated with several cancers, such as Ewing sarcoma and AML [Wang Y et al. (2023) Nat Chem Biol 19, 1223–1234; Chandra B et al. (2022) Cancer Discov 12, 1152–1169]. Mutations in the histone acetylation “reader” eleven‐nineteen‐leukemia (ENL) have been shown to form discrete condensates at endogenous genomic targets, but it remains unclear how ENL mutations drive tumorigenesis and whether it is correlated with their condensate formation property. Liu et al. now show, using a conditional knock‐in mouse model, that ENL YEATS domain mutation is a bona fide oncogenic driver for AML. This mutant ENL forms condensates in hematopoietic stem/progenitor cells at the genomic loci of key leukemogenic genes, including Meis1 and Hoxa cluster genes, and disrupting condensate formation via mutagenesis impairs its chromatin and oncogenic function. Furthermore, they show that small‐molecule inhibition of the acetyl‐binding activity displaces ENL mutant condensates from oncogenic target loci, and this inhibitor significantly impairs the onset and progression of AML driven by mutant ENL in vivo.https://doi.org/10.1002/1878-0261.13731ENL YEATShistone modificationsTDI‐11055transcriptional condensatestumorigenesis |
| spellingShingle | Zhong Fan Yanan Jiang Xiaotian Zhang ENL mutation and AML: a new model that reveals oncogenic condensate's function in leukemogenesis Molecular Oncology ENL YEATS histone modifications TDI‐11055 transcriptional condensates tumorigenesis |
| title | ENL mutation and AML: a new model that reveals oncogenic condensate's function in leukemogenesis |
| title_full | ENL mutation and AML: a new model that reveals oncogenic condensate's function in leukemogenesis |
| title_fullStr | ENL mutation and AML: a new model that reveals oncogenic condensate's function in leukemogenesis |
| title_full_unstemmed | ENL mutation and AML: a new model that reveals oncogenic condensate's function in leukemogenesis |
| title_short | ENL mutation and AML: a new model that reveals oncogenic condensate's function in leukemogenesis |
| title_sort | enl mutation and aml a new model that reveals oncogenic condensate s function in leukemogenesis |
| topic | ENL YEATS histone modifications TDI‐11055 transcriptional condensates tumorigenesis |
| url | https://doi.org/10.1002/1878-0261.13731 |
| work_keys_str_mv | AT zhongfan enlmutationandamlanewmodelthatrevealsoncogeniccondensatesfunctioninleukemogenesis AT yananjiang enlmutationandamlanewmodelthatrevealsoncogeniccondensatesfunctioninleukemogenesis AT xiaotianzhang enlmutationandamlanewmodelthatrevealsoncogeniccondensatesfunctioninleukemogenesis |