American Association for Cancer Research
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Supplementary Data from Small-Molecule Inhibition of the Acyl-Lysine Reader ENL as a Strategy against Acute Myeloid Leukemia

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posted on 2023-04-04, 00:20 authored by Yiman Liu, Qinglan Li, Fatemeh Alikarami, Declan R. Barrett, Leila Mahdavi, Hangpeng Li, Sylvia Tang, Tanweer A. Khan, Mayako Michino, Connor Hill, Lele Song, Lu Yang, Yuanyuan Li, Sheela Pangeni Pokharel, Andrew W. Stamford, Nigel Liverton, Louis M. Renzetti, Simon Taylor, Gillian F. Watt, Tammy Ladduwahetty, Stacia Kargman, Peter T. Meinke, Michael A. Foley, Junwei Shi, Haitao Li, Martin Carroll, Chun-Wei Chen, Alessandro Gardini, Ivan Maillard, David J. Huggins, Kathrin M. Bernt, Liling Wan
Supplementary Data from Small-Molecule Inhibition of the Acyl-Lysine Reader ENL as a Strategy against Acute Myeloid Leukemia


National Cancer Institute (NCI)

United States Department of Health and Human Services

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NIH Office of the Director (OD)

Pew Charitable Trusts (Pew)

V Foundation for Cancer Research (VFCR)

American Society of Hematology (ASH)

Leukemia Research Foundation (LRF)



The chromatin reader eleven–nineteen leukemia (ENL) has been identified as a critical dependency in acute myeloid leukemia (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 the clinical translation of this approach. AML is a poor-prognosis disease for which new therapeutic approaches are desperately needed. We developed an orally bioavailable inhibitor of ENL, demonstrated its potent efficacy in MLL-rearranged and NPM1-mutated AML, and determined its mechanisms of action. These biological and chemical insights will facilitate both basic research and clinical translation.This article is highlighted in the In This Issue feature, p. 2483

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