Superior efficacy of co-targeting GFI1/KDM1A and BRD4 against AML and post-MPN secondary AML cells

Fiskus, Warren; Mill, Christopher; Nabet, Behnam; Perera, Dimuthu; Birdwell, Christine; Manshouri, Taghi; Lara, Bernardo H; Kadia, Tapan M.; DiNardo, Courtney D.; Takahashi, Koichi; Daver, Naval; Bose, Prithviraj; Masárová, Lucia; Pemmaraju, Naveen; Kornblau, Steven M.; Borthakur, Gautam; Montalban‐Bravo, Guillermo; Manero, Guillermo Garcia; Sharma, Sunil; Stubbs, Matthew C.; Su, Xiaoping; Green, Michael R.; Coarfa, Cristian; Verstovšek, Srđan; Khoury, Joseph D.; Vakoc, Christopher R.; Bhalla, Kapil N.

doi:10.1038/s41408-021-00487-3

Cited by 29 publications

(30 citation statements)

References 62 publications

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“…However, at the dose and exposure interval of SNDX-50469 utilized in present studies, intracellular depletion of Menin was not observed. Importantly, consistent with previous reports, our findings also confirm that treatment with MI SNDX-50469 induces differentiation, with upregulation of CD11b expression, associated with loss of viability of AML cells harboring MLL1-r and mtNPM1 [ 17 , 26 ]. Consistent with reported effects of DOT1L or DHODH (dihydroorotate dehydrogenase) [ 44 ], these findings indicate that MI treatment also overcomes differentiation blockage in AML cells with MLL1-r [ 17 , 44 ].…”

Section: Discussionsupporting

confidence: 92%

“…1 B, C). We also employed the dTAG-13 system to degrade Menin-FKBP12 F36V in MOLM13 cells, following near-complete KO of the endogenous Menin, to assess biologic effects in MOLM13 cells ectopically transduced with and expressing Menin-FKBP12 F36V [ 26 ]. A near-complete KO of the endogenous Menin was achieved by transducing two splice-blocking sgRNAs, one in the intron between exon 3 and exon 4 and the other in the intron between exon 5 and exon 6.…”

Section: Resultsmentioning

confidence: 99%

“…Additionally, SNDX-50469 treatment increased protein levels of MCL1 and BFL1 (gene product of BCL2A1), as well as of PUMA, NOXA and the myeloid differentiation-associated marker CD11b in MOLM13 and OCI-AML3 cells (Figs. 2 A, B and S1D , E) [ 26 , 28 , 29 ]. In OCI-AML3 cells, SNDX-50469 treatment also depleted Bcl-xL levels (Fig.…”

Section: Resultsmentioning

confidence: 99%

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Effective Menin inhibitor-based combinations against AML with MLL rearrangement or NPM1 mutation (NPM1c)

et al. 2022

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Treatment with Menin inhibitor (MI) disrupts the interaction between Menin and MLL1 or MLL1-fusion protein (FP), inhibits HOXA9/MEIS1, induces differentiation and loss of survival of AML harboring MLL1 re-arrangement (r) and FP, or expressing mutant (mt)-NPM1. Following MI treatment, although clinical responses are common, the majority of patients with AML with MLL1-r or mt-NPM1 succumb to their disease. Pre-clinical studies presented here demonstrate that genetic knockout or degradation of Menin or treatment with the MI SNDX-50469 reduces MLL1/MLL1-FP targets, associated with MI-induced differentiation and loss of viability. MI treatment also attenuates BCL2 and CDK6 levels. Co-treatment with SNDX-50469 and BCL2 inhibitor (venetoclax), or CDK6 inhibitor (abemaciclib) induces synergistic lethality in cell lines and patient-derived AML cells harboring MLL1-r or mtNPM1. Combined therapy with SNDX-5613 and venetoclax exerts superior in vivo efficacy in a cell line or PD AML cell xenografts harboring MLL1-r or mt-NPM1. Synergy with the MI-based combinations is preserved against MLL1-r AML cells expressing FLT3 mutation, also CRISPR-edited to introduce mtTP53. These findings highlight the promise of clinically testing these MI-based combinations against AML harboring MLL1-r or mtNPM1.

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Section: Discussionsupporting

confidence: 92%

Section: Resultsmentioning

confidence: 99%

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Effective Menin inhibitor-based combinations against AML with MLL rearrangement or NPM1 mutation (NPM1c)

et al. 2022

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“…Similar approaches have also revealed metabolic genes capable of influencing cellular commitment to apoptosis and sensitizing AML cells to venetoclax [ 82 , 85 ]. Finally, CRISPR high-throughput approaches have anticipated gene determinants to enhance the sensitivity of small molecules under development for AML treatment [ 45 , 73 , 242 ].…”

Section: Hematologic Dependency Map Through Crispr Screens: Essential...mentioning

confidence: 99%

High-Throughput CRISPR Screening in Hematological Neoplasms

Ancos-Pintado

Bragado-García

Morales

et al. 2022

Cancers

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CRISPR is becoming an indispensable tool in biological research, revolutionizing diverse fields of medical research and biotechnology. In the last few years, several CRISPR-based genome-targeting tools have been translated for the study of hematological neoplasms. However, there is a lack of reviews focused on the wide uses of this technology in hematology. Therefore, in this review, we summarize the main CRISPR-based approaches of high throughput screenings applied to this field. Here we explain several libraries and algorithms for analysis of CRISPR screens used in hematology, accompanied by the most relevant databases. Moreover, we focus on (1) the identification of novel modulator genes of drug resistance and efficacy, which could anticipate relapses in patients and (2) new therapeutic targets and synthetic lethal interactions. We also discuss the approaches to uncover novel biomarkers of malignant transformations and immune evasion mechanisms. We explain the current literature in the most common lymphoid and myeloid neoplasms using this tool. Then, we conclude with future directions, highlighting the importance of further gene candidate validation and the integration and harmonization of the data from CRISPR screening approaches.

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“…Prior work from our lab and others suggest that the combination of kinase and LSD1 inhibition may be an effective therapeutic strategy in AML (20)(21)(22)(23). To establish whether this approach is effective for FLT3-ITD AML, we treated FLT3-ITD-positive (MOLM13 and MV4-11) and FLT3-ITD-negative (K562) cell lines with multiple FLT3/LSD1 inhibitors.…”

Section: Combined Flt3/lsd1 Inhibition Synergistically Represses Myc ...mentioning

confidence: 99%

Disruption of the MYC Super-Enhancer Complex by Dual Targeting of FLT3 and LSD1 in Acute Myeloid Leukemia

Yashar

Curtiss

Coleman

et al. 2022

Preprint

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Clinical responses to kinase inhibitor therapy in acute myeloid leukemia (AML) are limited by the inevitable development of resistance. A major contributor to resistance is early epigenetic adaptation, leading to persistence of a small number of leukemia cells. Here we show that inhibition of the epigenetic regulator lysine-specific demethylase 1 (LSD1) augments the response to inhibitors of the FLT3 kinase in AML. We demonstrate that combined FLT3 and LSD1 inhibition results in synergistic cell death of FLT3-mutant AML cells. The drug combination activates a pro-differentiative epigenetic and transcriptional program while simultaneously suppressing the activity of MYC target genes. High-resolution, multi-modal epigenetic analyses revealed that combined FLT3 and LSD1 inhibition results in the suppression of MYC-bound promoters and the activation of PU.1-bound enhancers. Regulon enrichment analysis in primary AML samples nominated STAT5 as a putative regulator of MYC gene expression. Inhibition of FLT3 results in a loss of STAT5 binding at the MYC blood super-enhancer and a loss of super-enhancer activation. In contrast, LSD1 inhibition prevents the removal of repressive H3K9me1 marks at MYC target genes, resulting in suppression of MYC expression. We validated these findings in 66 primary AML samples including 17 FLT3-ITD-positive AML samples, with the majority demonstrating improved responses with the drug combination. High MYC regulon activity was a predictor of response to the drug combination and RNA-seq on drug-treated AML samples revealed suppression of MYC target genes. Finally, single cell ATAC-seq on primary AML blasts treated ex vivo with the FLT3 and LSD1 inhibitor combination results in a shift from MYC super-enhancer-high to a MYC super-enhancer-low cell state. Collectively, these studies provide preclinical rationale for the investigation of dual FLT3 and LSD1 inhibition in a clinical trial.

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Superior efficacy of co-targeting GFI1/KDM1A and BRD4 against AML and post-MPN secondary AML cells

Cited by 29 publications

References 62 publications

Effective Menin inhibitor-based combinations against AML with MLL rearrangement or NPM1 mutation (NPM1c)

Effective Menin inhibitor-based combinations against AML with MLL rearrangement or NPM1 mutation (NPM1c)

High-Throughput CRISPR Screening in Hematological Neoplasms

Disruption of the MYC Super-Enhancer Complex by Dual Targeting of FLT3 and LSD1 in Acute Myeloid Leukemia

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