Targeting of epigenetic co-dependencies enhances anti-AML efficacy of Menin inhibitor in AML with MLL1-r or mutant NPM1
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...
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| Format: | Article |
| Language: | English |
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Nature Publishing Group
2023-04-01
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| Series: | Blood Cancer Journal |
| Online Access: | https://doi.org/10.1038/s41408-023-00826-6 |
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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 |
| author_facet | 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 |
| author_sort | Warren Fiskus |
| collection | DOAJ |
| description | 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. |
| format | Article |
| id | doaj-art-ac5251edf70f45ea8914536e1354701b |
| institution | OA Journals |
| issn | 2044-5385 |
| language | English |
| publishDate | 2023-04-01 |
| publisher | Nature Publishing Group |
| record_format | Article |
| series | Blood Cancer Journal |
| spelling | doaj-art-ac5251edf70f45ea8914536e1354701b2025-08-20T01:52:24ZengNature Publishing GroupBlood Cancer Journal2044-53852023-04-0113111310.1038/s41408-023-00826-6Targeting of epigenetic co-dependencies enhances anti-AML efficacy of Menin inhibitor in AML with MLL1-r or mutant NPM1Warren Fiskus0Christopher P. Mill1Christine Birdwell2John A. Davis3Kaberi Das4Steffen Boettcher5Tapan M. Kadia6Courtney D. DiNardo7Koichi Takahashi8Sanam Loghavi9Michael J. Soth10Tim Heffernan11Gerard M. McGeehan12Xinjia Ruan13Xiaoping Su14Christopher R. Vakoc15Naval Daver16Kapil N. Bhalla17The University of Texas MD Anderson Cancer CenterThe University of Texas MD Anderson Cancer CenterThe University of Texas MD Anderson Cancer CenterThe University of Texas MD Anderson Cancer CenterThe University of Texas MD Anderson Cancer CenterUniversity of Zurich and University Hospital ZurichThe University of Texas MD Anderson Cancer CenterThe University of Texas MD Anderson Cancer CenterThe University of Texas MD Anderson Cancer CenterThe University of Texas MD Anderson Cancer CenterThe University of Texas MD Anderson Cancer CenterThe University of Texas MD Anderson Cancer CenterSyndax PharmaceuticalsThe University of Texas MD Anderson Cancer CenterThe University of Texas MD Anderson Cancer CenterCold Spring Harbor LaboratoryThe University of Texas MD Anderson Cancer CenterThe University of Texas MD Anderson Cancer CenterAbstract 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.https://doi.org/10.1038/s41408-023-00826-6 |
| spellingShingle | 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 Targeting of epigenetic co-dependencies enhances anti-AML efficacy of Menin inhibitor in AML with MLL1-r or mutant NPM1 Blood Cancer Journal |
| title | Targeting of epigenetic co-dependencies enhances anti-AML efficacy of Menin inhibitor in AML with MLL1-r or mutant NPM1 |
| title_full | Targeting of epigenetic co-dependencies enhances anti-AML efficacy of Menin inhibitor in AML with MLL1-r or mutant NPM1 |
| title_fullStr | Targeting of epigenetic co-dependencies enhances anti-AML efficacy of Menin inhibitor in AML with MLL1-r or mutant NPM1 |
| title_full_unstemmed | Targeting of epigenetic co-dependencies enhances anti-AML efficacy of Menin inhibitor in AML with MLL1-r or mutant NPM1 |
| title_short | Targeting of epigenetic co-dependencies enhances anti-AML efficacy of Menin inhibitor in AML with MLL1-r or mutant NPM1 |
| title_sort | targeting of epigenetic co dependencies enhances anti aml efficacy of menin inhibitor in aml with mll1 r or mutant npm1 |
| url | https://doi.org/10.1038/s41408-023-00826-6 |
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