Enhancer remodeling drives MLL oncogene-dependent transcriptional dysregulation in leukemia stem cells
| Autor: | Feng Pan, Masayuki Iwasaki, Wenqi Wu, Yanan Jiang, Xin Yang, Li Zhu, Zhigang Zhao, Michael L Cleary |
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| Rok vydání: | 2023 |
| Předmět: | |
| Zdroj: | Blood Advances. |
| ISSN: | 2473-9537 2473-9529 |
| Popis: | Acute myeloid leukemia (AML) with MLL gene rearrangement (MLLr) comprises a cellular hierarchy in which a subpopulation of cells serves as functional leukemia stem cells (LSCs). They are maintained by a unique gene expression program and chromatin states, which are thought to reflect the actions of enhancers. Here, we delineate the active enhancer landscape and observe pervasive enhancer malfunction in LSCs. Reconstruction of regulatory networks revealed a master set of hematopoietic transcription factors. We show that EP300 is an essential transcriptional coregulator for maintaining LSC oncogenic potential, as it controls essential gene expression through modulation of H3K27 acetylation and assessments of transcription factor dependencies. Moreover, the EP300 inhibitor A-485 affects LSC growth by targeting enhancer activity via histone acetyltransferase domain inhibition. Together, these data implicate a perturbed MLLr-specific enhancer accessibility landscape, suggesting the possibility for disruption of the LSC enhancer regulatory axis as a promising therapeutic strategy in AML. |
| Databáze: | OpenAIRE |
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