Faculty, Staff and Student Publications
Publication Date
1-9-2023
Journal
Cancer Discovery
Abstract
Menin interacts with oncogenic MLL1-fusion proteins, and small molecules that disrupt these associations are in clinical trials for leukemia treatment. By integrating chromatin-focused and genome-wide CRISPR screens with genetic, pharmacologic, and biochemical approaches, we discovered a conserved molecular switch between the MLL1-Menin and MLL3/4-UTX chromatin-modifying complexes that dictates response to Menin-MLL inhibitors. MLL1-Menin safeguards leukemia survival by impeding the binding of the MLL3/4-UTX complex at a subset of target gene promoters. Disrupting the Menin-MLL1 interaction triggers UTX-dependent transcriptional activation of a tumor-suppressive program that dictates therapeutic responses in murine and human leukemia. Therapeutic reactivation of this program using CDK4/6 inhibitors mitigates treatment resistance in leukemia cells that are insensitive to Menin inhibitors. These findings shed light on novel functions of evolutionarily conserved epigenetic mediators like MLL1-Menin and MLL3/4-UTX and are relevant to understand and target molecular pathways determining therapeutic responses in ongoing clinical trials.
Keywords
Humans, Mice, Animals, Myeloid-Lymphoid Leukemia Protein, Histone-Lysine N-Methyltransferase, Cell Line, Tumor, Transcription Factors, Leukemia, Chromatin, Mammals
DOI
10.1158/2159-8290.CD-22-0416
PMID
36264143
PMCID
PMC9827117
PubMedCentral® Posted Date
October 2022
PubMedCentral® Full Text Version
Post-print
Published Open-Access
yes
Included in
Bioinformatics Commons, Biomedical Informatics Commons, Medical Molecular Biology Commons, Oncology Commons