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Wilms tumor-associated ENL mutants promote MOZ/MORF-mediated DOT1L loading in kidney tumor and leukemia

ABSTRACT: ENL is mutated in both Wilms tumor and leukemia which are the two major types of childhood cancers that occur at an early age. This study demonstrates that ENL mutants promote the loading of the DOT1L complex onto promoters in a MOZ/MORF histone acetyltransferase- dependent manner. The ENL protein is an epigenetic hub that interacts with multiple functionally distinct protein complexes to regulate transcription. MOZ binds to ENL through its YEATS domain to form a MOZ/ENL complex, which further recruits a DOT1L/AF10 complex and loads the ENL/DOT1L/AF10 complex onto nearby chromatin. Small indels in the YEATS domain increase the affinity to MOZ/MORF, which potentiates the interaction with ENL and the loading of the DOT1L complex, thereby hyperactivating HOX gene expression in embryonic kidney cells and hematopoietic cells. This oncogenic transformation can be suppressed by inhibitors of the histone-modifying activities of MOZ/MORF and DOT1L, paving the way for molecular targeted therapies against ENL-mutated cancers.

ORGANISM(S): Homo Sapiens (human)

SUBMITTER: Akihiko Yokoyama

PROVIDER: PXD053676 | JPOST Repository | Sat Jul 05 00:00:00 BST 2025

REPOSITORIES: jPOST

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			Action	DRS
	293T_Vector_FLAG.mgf	Mgf
	293T_Vector_FLAG.mzid	Mzid
	293T_Vector_FLAG.raw	Raw
	293T_fENL_FLAG.mgf	Mgf
	293T_fENL_FLAG.mzid	Mzid

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