Enhancer remodeling drives MLL oncogene-dependent transcriptional dysregulation in leukemia stem cells

Blood Advances - Tập 7 - Trang 2504-2519 - 2023
Feng Pan1, Masayuki Iwasaki1,2, Wenqi Wu3, Yanan Jiang3, Xin Yang1, Li Zhu1, Zhigang Zhao3, Michael L. Cleary1
1Department of Pathology, Stanford University, Stanford, CA
2Department of Advanced Health Science, Institute of Laboratory Animals, Tokyo Women's Medical University, Tokyo, Japan
3Department of Hematology, Tianjin Medical University Cancer Institute and Hospital, National Clinical Research Center for Cancer, Key Laboratory of Cancer Prevention and Therapy, Tianjin's Clinical Research Center for Cancer, Tianjin, People’s Republic of China

Tóm tắt

Abstract Acute myeloid leukemia (AML) with mixed-lineage leukemia (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 because 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.

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Blood Advances

Tập 7

2504-2519

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