Article ; Online: A Molecular Switch between Mammalian MLL Complexes Dictates Response to Menin-MLL Inhibition.
2022 Volume 13, Issue 1, Page(s) 146–169
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 ... ...
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. Significance: Menin-MLL inhibitors silence a canonical HOX- and MEIS1-dependent oncogenic gene expression program in leukemia. We discovered a parallel, noncanonical transcriptional program involving tumor suppressor genes that are repressed in Menin-MLL inhibitor-resistant leukemia cells but that can be reactivated upon combinatorial treatment with CDK4/6 inhibitors to augment therapy responses. This article is highlighted in the In This Issue feature, p. 1. |
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MeSH term(s) | Humans ; Mice ; Animals ; Myeloid-Lymphoid Leukemia Protein/genetics ; Histone-Lysine N-Methyltransferase/genetics ; Histone-Lysine N-Methyltransferase/metabolism ; Cell Line, Tumor ; Transcription Factors/genetics ; Leukemia/drug therapy ; Chromatin ; Mammals/genetics ; Mammals/metabolism |
Chemical Substances | Myeloid-Lymphoid Leukemia Protein (149025-06-9) ; Histone-Lysine N-Methyltransferase (EC 2.1.1.43) ; Transcription Factors ; Chromatin |
Language | English |
Publishing date | 2022-10-21 |
Publishing country | United States |
Document type | Journal Article ; Research Support, Non-U.S. Gov't ; Research Support, N.I.H., Extramural |
ZDB-ID | 2625242-9 |
ISSN | 2159-8290 ; 2159-8274 |
ISSN (online) | 2159-8290 |
ISSN | 2159-8274 |
DOI | 10.1158/2159-8290.CD-22-0416 |
Database | MEDical Literature Analysis and Retrieval System OnLINE |
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