期刊
CANCER DISCOVERY
卷 12, 期 11, 页码 2684-2709出版社
AMER ASSOC CANCER RESEARCH
DOI: 10.1158/2159-8290.CD-21-1307
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资金
- Rockefeller University
- Leukemia & Lymphoma Society
- St. Jude Children's Research Hospital Collaborative Initiative on Chromatin Regulation in Pediatric Cancer
- Tri-Institutional Therapeutics Discovery Institute (TDI)
- Takeda Pharmaceutical Company
- Memorial Sloan Kettering Cancer Center, The Rockefeller University
- Weill Cornell Medicine
- NIH Director's New Innovator Award [1DP2HG012443]
- NIH Pathway to Independence Award [R00CA226399]
- Pew-Stewart Scholar Award
- V Foundation Scholar Award
- American Society of Hematology Scholar Award
- Leukemia Research Foundation grant
- SU2C and Cancer Research UK [RT617]
- Biff Ruttenberg Foundation
The small-molecule inhibitor TDI-11055 effectively targets AML with MLL rearrangements or NPM1 mutations by displacing ENL from chromatin and impairing transcription elongation. This study provides a promising epigenetic therapy for specific subsets of AML and supports its clinical translation.
The chromatin reader eleven-nineteen leukemia (ENL) has been identifi ed 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 treat-ment rapidly decreases chromatin occupancy of ENL-associated complexes and impairs transcription elongation, leading to suppression of key oncogenic gene expression programs and induction of dif-ferentiation. 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 defi ned AML subsets and support the clinical translation of this approach.SIGNIFICANCE: AML is a poor-prognosis disease for which new therapeutic approaches are desper-ately needed. We developed an orally bioavailable inhibitor of ENL, demonstrated its potent effi cacy 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.
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