Browse
Submit Data
Databases
API
Help

Dataset Information

0 Views

0 Connections

0 Citations

0 Reanalyses

0 Downloads

Omics score: 0

Synergistic Interaction Between the LSD1 Inhibitor T-3775440 and the NEDD8-activating Enzyme Inhibitor Pevonedistat (TAK-924/MLN4924) Promotes Anti-Acute Myeloid Leukemia Effects

ABSTRACT: Lysine-specific demethylase 1A (LSD1) specifically demethylates di- and monomethylated histone H3K4 or K9, resulting in context-dependent transcriptional repression or activation. We previously identified an irreversible LSD1 inhibitor T-3775440, which exerts antileukemic activities in a subset of acute myeloid leukemia (AML) cell lines by inducing cell transdifferentiation. The NEDD8-activating enzyme inhibitor pevonedistat (MLN4924, TAK-924) is an investigational drug with antiproliferative activities in AML, and is also reported to induce cell differentiation. We therefore tested the combination of these two agents in AML models.The combination treatment resulted in synergistic growth inhibition of AML cells, accompanied by enhanced transdifferentiation and suppression of the leukemic stem cell gene signature.

ORGANISM(S): Homo sapiens

PROVIDER: GSE89637 | GEO | 2017/06/30

SECONDARY ACCESSION(S): PRJNA352778

REPOSITORIES: GEO

ACCESS DATA

Json Xml

Shared Molecules

Only show the datasets with similarity scores above: 0.5

Threshold

0.5

Similar Datasets

A novel LSD1 inhibitor T-3775440 induces transdifferentiation in AML cell lines

Project description:We describe the anti-leukemic activity and mechanism of action of T-3775440, a novel irreversible LSD1 inhibitor. Cell growth analysis of leukemia cell lines revealed that acute erythroleukemia (AEL) and acute megakaryoblastic leukemia cells (AMKL) are highly sensitive to this compound. T-3775440 treatment enforced transdifferentiation-like phenotypic change from erythroid/megakaryocytic lineages into granulomonocytic lineage. Our findings provide the rationale for testing LSD1 inhibitors as potential treatments with a novel mechanism of action for AML, particularly AEL and AMKL.

2017-01-01 | GSE87580 | GEO

Homo sapiens

Project description:Synergistic Interaction Between the LSD1 Inhibitor T-3775440 and the NEDD8-activating Enzyme Inhibitor Pevonedistat (TAK-924/MLN4924) Promotes Anti-Acute Myeloid Leukemia Effects

| PRJNA352778 | ENA

Expression profiling of CLL derived T Cells treated with pevonedistat

Project description:Novel targeted agents used in therapy of lymphoid malignancies, such as inhibitors of B-cell receptor-associated kinases, are recognized to have complex immune-mediated effects. NEDD8-activating enzyme (NAE) has been identified as a tractable target in chronic lymphocytic leukemia (CLL) and non-Hodgkin lymphoma. We and others have shown that pevonedistat (TAK-924), a small molecule inhibitor of NAE, abrogates NF-κB signaling in malignant B cells. However, NF-κB pathway activity is indispensable in immune response, and T-cell function is altered in patients with CLL. Using T cells derived from patients with CLL, we demonstrate that while targeting NAE results in markedly differential expression of NF-κB-regulated genes and downregulation of IL-2 signaling during T-cell activation, T cells evade apoptosis. Meanwhile, NAE inhibition favorably modulates polarization of T cells in vitro, with decreased Treg differentiation and a shift towards TH1 phenotype, accompanied by increased interferon-γ production. These findings were recapitulated in vivo in immunocompetent mouse models. T cells exposed to pevonedistat in washout experiments, informed by its human pharmacokinetic profile, recover NAE activity and maintain their response to T-cell receptor stimulation and cytotoxic potential. Our data shed light on the potential immune implications of targeting neddylation in CLL and lymphoid malignancies.

2019-10-08 | GSE138560 | GEO

Targeting neddylation and sumoylation in chemoresistant triple negative breast cancer

Project description:Triple negative breast cancer (TNBC) accounts for 15-20% of breast cancer cases in the United States. Systemic neoadjuvant chemotherapy (NACT), with or without immunotherapy, is the current standard of care for patients with early-stage TNBC. However, up to 70% of TNBC patients have significant residual disease once NACT is completed, which is associated with a high risk of developing recurrence within two to three years of surgical resection. To identify targetable vulnerabilities in chemoresistant TNBC, we generated longitudinal patient-derived xenograft (PDX) models from TNBC tumors before and after patients received NACT. We then compiled transcriptomes and drug response profiles for all models. Transcriptomic analysis identified the enrichment of aberrant protein homeostasis pathways in models from post-NACT tumors relative to pre-NACT tumors. This observation correlated with increased sensitivity in vitro to inhibitors targeting the proteasome, heat shock proteins, and neddylation pathways. Pevonedistat, a drug annotated as a NEDD8-activating enzyme (NAE) inhibitor, was prioritized for validation in vivo and demonstrated efficacy as a single agent in multiple PDX models of TNBC. Pharmacotranscriptomic analysis identified a pathway-level correlation between pevonedistat activity and post-translational modification (PTM) machinery, particularly involving neddylation and sumoylation targets. Elevated levels of both NEDD8 and SUMO1 were observed in models exhibiting a favorable response to pevonedistat compared to those with a less favorable response in vivo. Moreover, a correlation emerged between the expression of neddylation-regulated pathways and tumor response to pevonedistat, indicating that targeting these PTM pathways may prove effective in combating chemoresistant TNBC.

2024-05-17 | GSE264252 | GEO

RNA-seq of MV-4-11 or THP-1 cells treated with LSD1 inhibitor INCB059872

Project description:INCB059872 is a selective irreversible inhibitor of Lysine-Specific Demethylase 1 (LSD1) that is in phase 1 clinical trials in hematopoietic malignancies. LSD1 inhibition can induce differentiation of acute myeloid leukemia (AML), and here we have used RNA-seq to measure the transcriptional changes caused by INCB059872 in two AML cell lines.

2020-05-28 | GSE145106 | GEO

Targeted inhibition of GFI1/KDM1A combined with BET inhibitor augments lethal activity against AML including post-MPN sAML cells [RNA-seq]

Project description:To determine the impact of inhibition of KDM1A/LSD1 through genetic manipulation by CRISPR/Cas9 or inducible shRNA or following treatment with irreversible LSD1 inhibitor INCB059872 on global transcriptomic profile in AML and post-MPN sAML cells. To determine the impact of GFI1 knockdown on global transcriptomic profile in AML cells.

2021-05-26 | GSE160303 | GEO

HMG20B stabilizes interaction of LSD1 with GFI1 on chromatin to confer 1 transcription repression and leukemia cell differentiation block

Project description:Pharmacologic inhibition of LSD1 induces molecular and morphologic differentiation of blast cells in acute myeloid leukaemia (AML) patients harboring MLL gene translocations. In addition to its demethylase activity, LSD1 has a critical scaffolding function at genomic sites occupied by the SNAG domain transcription repressor GFI1. Importantly, inhibitors block both enzymatic and scaffolding activities, in the latter case by disrupting the protein:protein interaction of GFI1 with LSD1. To explore the wider consequences of LSD1 inhibition on the LSD1 protein complex we made use of mass spectrometry approaches. We discovered that the interaction of the HMG-box protein HMG20B with LSD1 was also disrupted by LSD1 inhibition. Downstream investigations revealed that HMG20B is colocated on chromatin genome-wide with GFI1 and LSD1; the strongest HMG20B binding colocates with the strongest GFI1 and LSD1 binding. Functional assays demonstrated that HMG20B depletion induces leukaemia cell differentiation and further revealed that HMG20B is required for the transcription repressor activity of GFI1 through stabilizing the interaction on chromatin of LSD1 with GFI1. Interaction of HMG20B with LSD1 is through its coiled-coil domain. Thus, HMG20B is a critical component of the GFI1:LSD1 transcription repressor complex which contributes to leukaemia cell differentiation block.

2023-03-11 | PXD030581 | Pride

Multigenerational cell tracking of DNA replication and heritable DNA damage

Project description:The goal of this project was to analyze gene expression changes upon polyploidization. To this end, human U-2 OS cells were exposed to the NEDD8-activating enzyme (NAE) inhibitor Pevonedistat (MLN4924), a first-in-class anticancer drug that induces DNA re-replication, or to oncogenic H-RAS V12 (HRAS) over-expression. Untreated U-2 OS cells served as control. Cells with 2N-4N DNA content were separated from cells with >4N DNA content by FACS and single cells were sorted into 384 well plates for scRNA-seq analysis.

2025-03-31 | GSE255874 | GEO

Targeted inhibition of GFI1/KDM1A combined with BET inhibitor augments lethal activity against AML including post-MPN sAML cells [ChIP-seq]

Project description:To determine the impact of inhibition of KDM1A/LSD1 through genetic manipulation or with irreversible LSD1 inhibitors on global chromatin accessibility and occupancy of H3K27Ac and BRD4 in AML and post-MPN sAML cells.

2021-05-26 | GSE160318 | GEO

Targeted inhibition of GFI1/KDM1A combined with BET inhibitor augments lethal activity against AML including post-MPN sAML cells [ATAC-seq]

2021-05-26 | GSE160309 | GEO