Protein ENL (MLLT1) (ENL)

Protein ENL, encoded by the MLLT1 gene, is a crucial epigenetic reader and a core component of the Super Elongation Complex (SEC) [1, 6]. It features a highly conserved YEATS domain that specifically recognizes and binds to acetylated and crotonylated lysine residues on histone tails, such as H3K9ac and H3K27ac [4, 13]. This interaction is essential for recruiting the SEC and other transcriptional co-activators, including DOT1L, to gene promoters and enhancers to facilitate RNA polymerase II elongation [1, 2]. In clinical contexts, ENL is frequently involved in chromosomal translocations, particularly forming the MLL-ENL fusion protein associated with aggressive acute myeloid and lymphoid leukemias [1, 7]. These fusions lead to the constitutive activation of oncogenic gene programs, including the overexpression of MYC and HOX cluster genes [4, 8]. Beyond leukemias, mutations in the ENL YEATS domain have also been identified as drivers in Wilms tumors [9]. Consequently, ENL has emerged as a promising therapeutic target, with research focusing on small-molecule inhibitors and PROTAC degraders that block its reader function [4, 13]. Such interventions aim to selectively suppress oncogenic transcription while sparing normal cellular processes [2, 4].

Other names

MLLT1YEATS1LTG19Eleven-nineteen leukemia proteinMyeloid/lymphoid or mixed-lineage leukemia; translocated to, 1Super elongation complex subunit MLLT1

Inhibition of the YEATS domain to prevent binding to acetylated or crotonylated histones (e.g., H3K9ac, H3K27ac), thereby disrupting the recruitment of the Super Elongation Complex (SEC) and DOT1L to oncogenic target genes.