Targeting of Epigenetic Co-dependencies Enhances Anti-AML Efficacy of Menin Inhibitor in AML with MLL1-R or Mutant NPM1

Authors

Warren Fiskus
Christopher P Mill
Christine Birdwell
John A Davis
Kaberi Das
Steffen Boettcher
Tapan M Kadia
Courtney D DiNardo
Koichi Takahashi
Sanam Loghavi
Michael J Soth
Tim Heffernan
Gerard M McGeehan
Xinjia Ruan
Xiaoping Su
Christopher R Vakoc
Naval Daver
Kapil N Bhalla

Publication Date

4-13-2023

Journal

Blood Cancer Journal

DOI

10.1038/s41408-023-00826-6

PMID

37055414

PMCID

PMC10102188

PubMedCentral® Posted Date

4-13-2023

PubMedCentral® Full Text Version

Post-print

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.

Keywords

Humans, Cell Cycle Proteins, Epigenesis, Genetic, Histone Demethylases, Histone-Lysine N-Methyltransferase, Leukemia, Myeloid, Acute, Myeloid-Lymphoid Leukemia Protein, Neoplasm Recurrence, Local, Nuclear Proteins, Proto-Oncogene Proteins, Transcription Factors

Comments

This article has been corrected. See Blood Cancer J. 2025 May 21;15(1):99.

Published Open-Access

yes

Recommended Citation

Fiskus, Warren; Mill, Christopher P; Birdwell, Christine; et al., "Targeting of Epigenetic Co-dependencies Enhances Anti-AML Efficacy of Menin Inhibitor in AML with MLL1-R or Mutant NPM1" (2023). Faculty, Staff and Student Publications. 608.
https://digitalcommons.library.tmc.edu/uthgsbs_docs/608