DOT1L inhibition blocks multiple myeloma cell proliferation through suppressing IRF4-MYC signaling
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ABSTRACT:
PROVIDER: PRJNA428234 | ENA |
REPOSITORIES: ENA
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Project description:Epigenetic alterations play an important role in the pathogenesis in multiple myeloma (MM), but its biological and clinical relevance is not fully understood. Here, we show that DOT1L, which catalyzes methylation of histone H3 lysine 79, is required for the survival of MM cells. Treatment with DOT1L inhibitors induced cell cycle arrest and apoptosis in MM cells, and strongly suppressed cell proliferation in vitro. Chromatin immunoprecipitation-sequencing (ChIP-seq) and microarray analysis revealed that DOT1L inhibition downregulated H3K79 dimethylation (H3K79me2) and expression levels of IRF4-MYC signaling genes in MM cells. Our data suggest that DOT1L may play an essential role in the development of MM, and DOT1L inhibition may provide a new therapy for MM treatment.
2018-09-23 | GSE108661 | GEO
Project description: Not available
| S-EPMC6312027 | biostudies-literature
Project description:The goal of this gene expression study was to identify genes whose expression depends on the transription factor IRF4 by knocking down it's expression using shRNA in two IRF4+ myeloma cell lines. Keywords: time series design Two myeloma lines were analyzed over a time course of IRF4-targeted shRNA induction. There are 3 time courses: two using KMS12 (biological replicates) and one with SKMM1. Within each time course there are technical replicates.
2010-05-26 | E-GEOD-9067 | biostudies-arrayexpress
Project description:Using RNA interference to identify IRF4 target genes. Keywords: time series design
2008-07-07 | GSE8958 | GEO
Project description:Using RNA interference to identify IRF4 target genes. Keywords: time series design Gene expression was analyzed using Lymphochip cDNA spotted arrays. Myeloma cell lines were infected with control (shluc, Cy3) or shIRF4 (Cy5) constructs, and changes in gene expression were monitored over time after induction of the shRNA with doxycyclin.
2008-07-07 | E-GEOD-8958 | biostudies-arrayexpress
Project description:The goal of this gene expression study was to identify genes whose expression depends on the transription factor IRF4 by knocking down it's expression using shRNA in two IRF4+ myeloma cell lines. Keywords: time series design
2008-07-07 | GSE9067 | GEO
Project description:Multiple myeloma (MM) is an incurable malignancy of plasma cells that exploits transcriptional networks driven by IRF4. To discover unique molecular vulnerabilities in MM centered on IRF4, we employ a multi-omics approach integrating functional genomics screening, spatial proteomics, and global chromatin mapping. We find that ARID1A, a member of the SWI/SNF chromatin remodeling complex, is both required for IRF4 expression and functionally associated with IRF4 protein on chromatin. Deletion of Arid1a in activated murine B cells thwarts subsequent plasma cell differentiation by disrupting IRF4-dependent transcriptional networks, therefore defining ARID1A as a novel plasma cell vulnerability. Targeting ARID1A-dependent SWI/SNF activity via SMARCA2/4 inhibition induces a rapid loss of IRF4-target gene expression and quenches global amplification of oncogenic gene expression driven by MYC, resulting in profound toxicity to MM cells. Notably, MM patients with aggressive disease have markers of SWI/SNF activity, and SMARCA2/4 inhibitors retain their activity in immunomodulatory drug (IMiD)-resistant MM cells. To fully harness the potential of these drugs, we use combinatorial drug screens to uncover profound synergistic toxicity between SMARCA2/4 and MEK inhibitors. Thus, targeting SWI/SNF activity potently represses an IRF4-MYC feed forward loop and provides a feasible path to effectively treat this incurable disease.
2024-01-11 | MSV000093842 | MassIVE
Project description:Multiple myeloma (MM) cells are addicted to MYC and its direct transactivation target IRF4 for proliferation and survival. MYC and IRF4 are still considered “undruggable” as the majority of small molecule inhibitors suffers from low potency, suboptimal pharmacokinetic properties and undesirable off-target effects. Indirect inhibition of MYC/IRF4 emerges as a therapeutic vulnerability in MM. Here, we uncover an unappreciated tumor suppressive role of C-terminal Binding Protein 2 (CTBP2) in MM via strong inhibition of the MYC-IRF4 axis. In contrast to epithelial cancers, CTBP2 is frequently downregulated in MM, in association with shortened survival, hyperproliferative features and adverse clinical outcomes. Restoration of CTBP2 exhibited potent anti-tumor effects against MM in vitro and in vivo, with marked repression of MYC-IRF4 network genes. Mechanistically, CTBP2 impeded transcription of MYC and IRF4 by histone H3 lysine 27 deacetylation (H3K27ac), and indirectly via activation of MYC repressor IFIT3. In addition, activation of interferon gene signature by CTBP2 suggested its concomitant immunomodulatory role in MM. Epigenetic studies revealed contribution of polycomb-mediated silencing and DNA methylation to CTBP2 inactivation in MM. Notably, inhibitors of Enhance of zeste homolog 2 (EZH2), histone deacetylase (HDACs) and DNA methyltransferase (DNMTs) currently under evaluation in clinical trials were effective in restoring CTBP2 expression in MM. Our findings indicated that loss of CTBP2 plays an essential role in myelomagenesis and decipher an additional mechanistic link on MYC-IRF4 dysregulation in MM. We envision that identification of novel critical regulators would facilitate the development of selective and effective approaches for treating this MYC/IRF4-addicted malignancy.
2024-03-10 | GSE255266 | GEO
Project description:Cell lines bearing MLL translocations (MV4-11 and MOLM-13) were treated with a potent, selective inhibitor of the DOT1L histone methyl transferase. Treatment of MLL-rearranged cell lines with the DOT1L inhibitor selectively inhibits H3K79 methylation and blocks expression of leukemogenic genes. Here we provide expression profiling data of cells treated with DOT1L inhibitor or vehicle control. MV4-11 cells were treated with 3 uM EPZ004777 (DOT1L inhibitor) or vehicle control (0.1% DMSO) for 2, 4 and 6 days. MOLM-13 cells were treated with 3 uM EPZ004777 (DOT1L inhibitor) or vehicle control (0.1% DMSO) for 6 days. For each unique conditon, 3 biological replicates were generated for expression profiling.
2011-07-11 | E-GEOD-29828 | biostudies-arrayexpress
Project description:To identify IRF4 transcription factor binding on chromatin at 5' regulatory regions of genes in myeloma cell line models. Keywords: binding site identification design Formaldehyde cross-linked, sonicated chromatin is prepared from cell lines Kms12 (test) and Ly19 (control). Chromatin immunoprecipated with anti-IRF4 antibody is labeled with Cy5 and co-hybridized on Agilent Human Promoter Set arrays with chromatin immunoprecipated with normal sera labeled with Cy3 . Two biological replicates were performed for the Kms12 and Ly19 experiments.
2010-05-25 | E-GEOD-9367 | biostudies-arrayexpress