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Can I read Targeting of epigenetic co-dependencies enhances anti-AML efficacy of Menin inhibitor in AML with MLL1-r or mutant NPM1 on EtoBox?
Targeting of epigenetic co-dependencies enhances anti-AML efficacy of Menin inhibitor in AML with MLL1-r or mutant NPM1 by 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 is a Medicine article available to read on EtoBox.
What is Targeting of epigenetic co-dependencies enhances anti-AML efficacy of Menin inhibitor in AML with MLL1-r or mutant NPM1 about?
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 mode
Who reads Targeting of epigenetic co-dependencies enhances anti-AML efficacy of Menin inhibitor in AML with MLL1-r or mutant NPM1?
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- Author
- 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
- Publisher
- Springer Science and Business Media LLC
- Published
- 2023
- Language
- EN
- Field
- Medicine (Health Sciences)