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ETV4-Dependent Transcriptional Plasticity Maintains MYC Expression and Results in IMiD Resistance in Multiple Myeloma [RNA-seq]

ABSTRACT: ETV4-Dependent Transcriptional Plasticity Maintains MYC Expression and Results in IMiD Resistance in Multiple Myeloma [RNA-seq]

PROVIDER: PRJNA1032930 | ENA |

REPOSITORIES: ENA

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			Action	DRS
	SRR26549823.fastq.gz	Fastqsanger.gz
	SRR26549824.fastq.gz	Fastqsanger.gz
	SRR26549825.fastq.gz	Fastqsanger.gz
	SRR26549826.fastq.gz	Fastqsanger.gz
	SRR26549827.fastq.gz	Fastqsanger.gz

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ETV4-Dependent Transcriptional Plasticity Maintains MYC Expression and Results in IMiD Resistance in Multiple Myeloma [RNA-seq]

Project description:Immunomodulatory Drugs (IMiDs) are a backbone therapy for multiple myeloma (MM). Despite their efficacy, most patients develop resistance and the mechanism(s) are not fully defined. Here, we show that IMiD responses are directed by IMiD-dependent degradation of IKZF1 and IKZF3 that bind to enhancers necessary to sustain the expression of MYC and other myeloma oncogenes. IMiD treatment universally depleted chromatin-bound IKZF1, but eviction of P300 and BRD4 co-activators only occurred in IMiD-sensitive cells. IKZF1-bound enhancers overlapped other transcription factor-binding motifs, including ETV4. ChIP-seq showed that ETV4 bound to the same enhancers as IKZF1, and ETV4 CRISPR/Cas9-mediated ablation resulted in sensitization of IMiD-resistant MM. ETV4 expression is associated with IMiD resistance in cell lines, poor prognosis in patients, and upregulated at relapse. These data indicate that ETV4 alleviates IKZF1 and IKZF3 dependency in MM by maintaining oncogenic enhancer activity and identify transcriptional plasticity as a previously unrecognized mechanism of IMiD resistance.

2023-10-30 | GSE246435 | GEO

ETV4-Dependent Transcriptional Plasticity Maintains MYC Expression and Results in IMiD Resistance in Multiple Myeloma [ChIP-seq]

2023-10-30 | GSE246429 | GEO

ETV4-Dependent Transcriptional Plasticity Maintains MYC Expression and Results in IMiD Resistance in Multiple Myeloma [ATAC-seq]

2023-10-30 | GSE246426 | GEO

ETV4-Dependent Transcriptional Plasticity Maintains MYC Expression and Results in IMiD Resistance in Multiple Myeloma

Project description:ETV4-Dependent Transcriptional Plasticity Maintains MYC Expression and Results in IMiD Resistance in Multiple Myeloma

| PRJNA1032929 | ENA

ETV4-Dependent Transcriptional Plasticity Maintains MYC Expression and Results in IMiD Resistance in Multiple Myeloma [ChIP-seq]

Project description:ETV4-Dependent Transcriptional Plasticity Maintains MYC Expression and Results in IMiD Resistance in Multiple Myeloma [ChIP-seq]

| PRJNA1032924 | ENA

ETV4-Dependent Transcriptional Plasticity Maintains MYC Expression and Results in IMiD Resistance in Multiple Myeloma [ATAC-seq]

Project description:ETV4-Dependent Transcriptional Plasticity Maintains MYC Expression and Results in IMiD Resistance in Multiple Myeloma [ATAC-seq]

| PRJNA1032919 | ENA

ETV4-Dependent Transcriptional Plasticity Maintains MYC Expression and Results in IMiD Resistance in Multiple Myeloma.

Project description:Immunomodulatory drugs (IMiD) are a backbone therapy for multiple myeloma (MM). Despite their efficacy, most patients develop resistance, and the mechanisms are not fully defined. Here, we show that IMiD responses are directed by IMiD-dependent degradation of IKZF1 and IKZF3 that bind to enhancers necessary to sustain the expression of MYC and other myeloma oncogenes. IMiD treatment universally depleted chromatin-bound IKZF1, but eviction of P300 and BRD4 coactivators only occurred in IMiD-sensitive cells. IKZF1-bound enhancers overlapped other transcription factor binding motifs, including ETV4. Chromatin immunoprecipitation sequencing showed that ETV4 bound to the same enhancers as IKZF1, and ETV4 CRISPR/Cas9-mediated ablation resulted in sensitization of IMiD-resistant MM. ETV4 expression is associated with IMiD resistance in cell lines, poor prognosis in patients, and is upregulated at relapse. These data indicate that ETV4 alleviates IKZF1 and IKZF3 dependency in MM by maintaining oncogenic enhancer activity and identify transcriptional plasticity as a previously unrecognized mechanism of IMiD resistance.SignificanceWe show that IKZF1-bound enhancers are critical for IMiD efficacy and that the factor ETV4 can bind the same enhancers and substitute for IKZF1 and mediate IMiD resistance by maintaining MYC and other oncogenes. These data implicate transcription factor redundancy as a previously unrecognized mode of IMiD resistance in MM. See related article by Welsh, Barwick, et al., p. 34. See related commentary by Yun and Cleveland, p. 5. This article is featured in Selected Articles from This Issue, p. 4.

| S-EPMC10772538 | biostudies-literature

ETV4-Dependent Transcriptional Plasticity Maintains MYC Expression and Results in IMiD Resistance in Multiple Myeloma

Project description:This SuperSeries is composed of the SubSeries listed below.

2023-10-29 | GSE246436 | GEO

CARM1 targeting potentiates IMiD activity: a novel approach to multiple myeloma therapy

Project description:Advancements in the treatment of multiple myeloma (MM) have resulted in significant improvement in the survival rate for patients <65, however not for patients >65. There is a particular need for improved therapies for this patient population. The protein arginine methyltransferase, CARM1 (coactivator associated arginine methyltransferase 1), is emerging as a potential cancer therapy target and inhibitors have been developed. MM cell lines are particularly dependent on CARM1 for cell survival. Here, we show that CARM1 targeting through a small molecule drug potentiates immunomodulatory drugs (IMiD) treatment in models of MM, likely through synergistic targeting of Aiolos (IKZF3) and MYC expression. Consistent with this, biorational development of a new molecule, 074, comprised of the CARM1 inhibitor, EZM2302, linked to the IMiD pomalidomide led to more potent killing of MM cells than either compound individually. 074 treatment or the combination of CARM1 knockdown (KD) with pomalidomide led to an upregulation of inflammation and interferon signaling pathways and downregulation of MYC signaling. Importantly, 074 reversed IMiD resistance characterized by MYC protein upregulation and cereblon (CRBN) protein downregulation. Taken together, our results demonstrate that dual CARM1/IKZF3-targeting agents represent a promising novel therapeutic strategy for MM and IMiD-resistant disease.

2025-05-06 | PXD046700 | Pride

Transcriptional heterogeneity overcomes super-enhancer disrupting drug combinations in multiple myeloma [ATAC-seq]

Project description:Multiple myeloma (MM) is a malignancy that is often driven by MYC and that is sustained by IRF4, which are upregulated by super-enhancers. IKZF1 and IKZF3 bind to super-enhancers and can be degraded using immunomodulatory imide drugs (IMiDs). Successful IMiD responses downregulate MYC and IRF4; however, this fails in IMiD-resistant cells. MYC and IRF4 downregulation can also be achieved in IMiD-resistant tumors using inhibitors of BET and EP300 transcriptional coactivator proteins; however, in vivo these drugs have a narrow therapeutic window. By combining IMiDs with EP300 inhibition, we demonstrate greater downregulation of MYC and IRF4, synergistic killing of myeloma in vitro and in vivo, and an increased therapeutic window. Interestingly, this potent combination failed where MYC and IRF4 expression was maintained by high levels of the AP-1 factor BATF. Our results identify an effective drug combination and a previously unrecognized mechanism of IMiD resistance.

2023-09-25 | GSE243978 | GEO

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