Small-molecule inhibition of the acyl-lysine reader ENL as a strategy against acute myeloid leukemia. Academic Article uri icon

Overview

abstract

  • The chromatin reader eleven-nineteen-leukemia (ENL) has been identified as a critical dependency in AML, but its therapeutic potential remains unclear. We describe a potent and orally bioavailable small-molecule inhibitor of ENL, TDI-11055, which displaces ENL from chromatin by blocking its YEATS domain interaction with acylated histones. Cell lines and primary patient samples carrying MLL rearrangements or NPM1 mutations are responsive to TDI-11055. A CRISPR-Cas9-mediated mutagenesis screen uncovers an ENL mutation that confers resistance to TDI-11055, validating the compound's on-target activity. TDI-11055 treatment rapidly decreases chromatin occupancy of ENL-associated complexes and impairs transcription elongation, leading to suppression of key oncogenic gene expression programs and induction of differentiation. In vivo treatment with TDI-11055 blocks disease progression in cell line and patient-derived xenograft models of MLL-rearranged and NPM1-mutated AML. Our results establish ENL displacement from chromatin as a promising epigenetic therapy for molecularly defined AML subsets and support clinical translation of this approach.

publication date

  • September 2, 2022

Research

keywords

  • Leukemia, Myeloid, Acute
  • Lysine

Identity

Digital Object Identifier (DOI)

  • 10.1158/2159-8290.CD-21-1307

PubMed ID

  • 36053276