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Targeting of epigenetic co-dependencies enhances anti-AML efficacy of Menin inhibitor in AML with MLL1-r or mutant NPM1.
- Source :
- Blood Cancer Journal; 4/13/2023, Vol. 13 Issue 1, p1-13, 13p
- Publication Year :
- 2023
-
Abstract
- Monotherapy with Menin inhibitor (MI), e.g., SNDX-5613, induces clinical remissions in patients with relapsed/refractory AML harboring MLL1-r or mtNPM1, but most patients either fail to respond or eventually relapse. Utilizing single-cell RNA-Seq, ChiP-Seq, ATAC-Seq, RNA-Seq, RPPA, and mass cytometry (CyTOF) analyses, present pre-clinical studies elucidate gene-expression correlates of MI efficacy in AML cells harboring MLL1-r or mtNPM1. Notably, MI-mediated genome-wide, concordant, log2 fold-perturbations in ATAC-Seq and RNA-Seq peaks were observed at the loci of MLL-FP target genes, with upregulation of mRNAs associated with AML differentiation. MI treatment also reduced the number of AML cells expressing the stem/progenitor cell signature. A protein domain-focused CRISPR-Cas9 screen in MLL1-r AML cells identified targetable co-dependencies with MI treatment, including BRD4, EP300, MOZ and KDM1A. Consistent with this, in vitro co-treatment with MI and BET, MOZ, LSD1 or CBP/p300 inhibitor induced synergistic loss of viability of AML cells with MLL1-r or mtNPM1. Co-treatment with MI and BET or CBP/p300 inhibitor also exerted significantly superior in vivo efficacy in xenograft models of AML with MLL1-r. These findings highlight novel, MI-based combinations that could prevent escape of AML stem/progenitor cells following MI monotherapy, which is responsible for therapy-refractory AML relapse. [ABSTRACT FROM AUTHOR]
- Subjects :
- ACUTE myeloid leukemia
EPIGENETICS
PROGENITOR cells
DISEASE remission
CELL survival
Subjects
Details
- Language :
- English
- ISSN :
- 20445385
- Volume :
- 13
- Issue :
- 1
- Database :
- Complementary Index
- Journal :
- Blood Cancer Journal
- Publication Type :
- Academic Journal
- Accession number :
- 171915666
- Full Text :
- https://doi.org/10.1038/s41408-023-00826-6