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E7820, an Anti-Cancer Sulfonamide, Degrades RBM39 in Patients with Splicing Factor Mutant Myeloid Malignancies: A Phase II Clinical Trial

ABSTRACT: E7820, an Anti-Cancer Sulfonamide, Degrades RBM39 in Patients with Splicing Factor Mutant Myeloid Malignancies: A Phase II Clinical Trial

PROVIDER: PRJNA944678 | ENA |

REPOSITORIES: ENA

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			Action	DRS
	SRR23864101_1.fastq.gz	Fastqsanger.gz
	SRR23864101_2.fastq.gz	Fastqsanger.gz
	SRR23864102_1.fastq.gz	Fastqsanger.gz
	SRR23864102_2.fastq.gz	Fastqsanger.gz
	SRR23864103_1.fastq.gz	Fastqsanger.gz

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E7820, an Anti-Cancer Sulfonamide, Degrades RBM39 in Patients with Splicing Factor Mutant Myeloid Malignancies: A Phase II Clinical Trial

Project description:Mutations in RNA splicing factor genes (SF3B1, SRSF2, and U2AF1) are common in AML and MDS and recent studies demonstrate pharmacologic degradation of the RNA splicing factor RBM39 results in preferential killing of splicing factor mutant cells. We therefore conducted a phase II clinical trial (NCT05024994) of the oral RBM39 degrader E7820 at the recommended phase II dose in patients with R/R MDS/AML and a splicing factor mutation. No patients met the primary endpoint of overall response rate in the first 12 patients enrolled, leading to study termination. However, E7820 was well-tolerated and achieved >50% RBM39 degradation in blood and disruption of splicing. At the same time, the degree of splicing disruption was far less than seen with in vitro doses exhibiting preclinical efficacy, providing potential explanation for limited clinical efficacy. Overall, this study demonstrates on-target safety and feasibility of RBM39 degradation in patients and supports future combination therapies with E7820.

2024-09-30 | GSE227343 | GEO

E7820, an anti-cancer sulfonamide, degrades RBM39 in patients with splicing factor mutant myeloid malignancies: a phase II clinical trial.

Project description: Not available

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The aryl sulfonamide indisulam inhibits acute megakaryoblastic leukemia (AMKL) by altering the alternative splicing of the transcription factor ZMYND8

Project description:Acute megakaryoblastic leukemia (AMKL) is a subtype of acute myeloid leukemia with clinical heterogeneity. The poor prognosis of AMKL means that new therapies need to be developed to treat this disease. Studies have shown that the dysregulation of alternative splicing is associated with the occurrence and development of AMKL and the increase of chemotherapy resistance. indisulam, as a synthetic aryl sulfonamide, can effectively treat solid tumors by targeting the splicing factor RBM39. However, the effects of indisulam on AMKL and the underlying molecular mechanisms remain to be thoroughly investigated. We first screened AMKL for indisulam susceptibility in a public drug-susceptibility database. The results showed that AMKL was more sensitive to insulin than other tumor types. We then treated human AMKL cell lines (CMK, MEG01 and M07e) with indisulam to evaluate its efficacy and investigate its molecular targets. The results suggest that indisulam induces RBM39 degradation and inhibits tumor growth in a dose-dependent manner. RNA-seq and proteomic analyses revealed that indisulam selectively degraded RBM39 and resulted in mis-splicing of the transcription factor ZMYND8, which maintains AML survival and proliferation. We knocked down ZMYND8 and confirmed the critical role of ZMYND8 in maintaining AMKL survival and proliferation. In addition, we verified that the anti-tumor effect of indisulam on AMKL was DCAF15 dependent. By targeting DCAF15 using CRISPR/Cas9 system, we confirmed the DCAF15-dependent effect of indisulam in both in vivo and in vitro models. Taken together, our study suggests that indisulam has promising therapeutic potential for AMKL by specifically targeting the splicing factor RBM39 and is dependent on the expression of DCAF15. In addition, our study identified ZMYND8 as a novel downstream regulator of RBM39 and the RBM39-ZMYND8 axis is important for AMKL survival and proliferation.

2025-04-23 | GSE266925 | GEO

RNA Expression Profiling of CD8+ T Cell-Enriched Peripheral Blood Mononuclear Cells from Potentiated Sulfonamide-Treated Patients with a Range of Lymphocyte Cytotoxicity Phenotypes

Project description:Hypersensitivity reactions are rare, but potentially severe adverse effects of sulfonamide antibiotics. Increased in vitro toxicity of lymphocytes, primarily CD8+ T cells, to sulfonamide drug metabolites as been proposed as a marker for sulfonamide hypersensitivity, but the mechanisms underlying this marker are unknown. Therefore, we used microarrays to compare RNA expression of CD8+ T cell-enriched peripheral blood mononuclear cells of human patients who have had a hypersensitivity (HS) reaction to sulfonamide antibiotics vs. patients who have been tolerant (TOL) to a course of sulfonamide antibiotics.

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Genome-wide chromatin occupancy of RBM39 and MLL1 in T47D cells

Project description:We report high-throughput profiling of RBM39 and MLL1 chromatin occupancy in T47D cells. By obtaining over four billion bases of sequence from chromatin immunoprecipitated DNA, we generated genome-wide chromatin-state maps of RBM39 and MLL1 in T47D cells. We found that more than 4500 regions were cofound by RBm39 and MLL1.

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Exceptional response of high-risk neuroblastoma to RBM39 degrader Indisulam (RNA-Seq)

Project description:Indisulam selectively bridges splicing factor RBM39 to DCAF15 for proteasomal degradation. However, clinical trials indicate that patient stratification based upon the mechanism of action of indisulam may be required to achieve the best response. Here we show that neuroblastoma, a MYC-driven cancer characterized by splicing dysregulation, requires RBM39 for survival, expresses high levels of DCAF15 among different solid tumor lineages, and is the most sensitive cancer lineage to indisulam that achieves therapeutic effect by specifically targeting RBM39 in neuroblastoma. Genetic depletion or proteasomal degradation of RBM39 by indisulam induces drastic splicing event changes in neuroblastoma cells. Through specifically targeting RBM39, indisulam induces exceptional tumor response in multiple high-risk neuroblastoma models. Collectively we demonstrate that high RBM39 dependency and high-level expression of DCAF15 provide indisulam a more efficacious therapeutic window to treating high-risk neuroblastoma.

2021-11-24 | GSE164505 | GEO

Exceptional response of high-risk neuroblastoma to RBM39 degrader Indisulam (ATAC-Seq)

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MORC2 regulates RBM39-mediated CDK5RAP2 alternative splicing to promote EMT and metastasis in colon cancer [RBM39 RIP-seq]

Project description:RNA immunoprecipitation sequencing (RIP-seq) for the detection of RBM39 protein-binding RNA in SW480 cells.

2024-08-02 | GSE246656 | GEO

RBM39 organizes an m⁶A-dependent silencing complex to degrade Tat mRNA and maintain HIV-1 latency

Project description:To further elucidate the interaction between RBM39 and its partern proteins, Flag-tagged RBM39 were transfected into HEK293T cells. After transfection, RBM39 and RBM39-bound proteins were enriched using anti-Flag beads. Subsequently, the enriched proteins were separated by SDS-PAGE and analyzed by LC-MS/MS.

2025-10-31 | PXD064858 | Pride

Global Regulation of Alternative RNA Splicing by the SR-Rich Protein RBM39

Project description:RBM39 is extensively involved in alternative splicing of RNA and helps regulate transcript levels. RBM39 may modulate alternative splicing similarly to U2AF65 by either directly binding to RNA or recruiting other splicing factors, such as U2AF65.

2016-09-13 | GSE86846 | GEO

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