Novel epigenetic based differentiation therapy for Acute Myeloid Leukemia
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ABSTRACT:
PROVIDER: PRJNA1114031 | ENA |
REPOSITORIES: ENA
Dataset's files
| Action | DRS | |||
|---|---|---|---|---|
| SRR29098259_1.fastq.gz | Fastqsanger.gz | |||
| SRR29098259_2.fastq.gz | Fastqsanger.gz | |||
| SRR29098260_1.fastq.gz | Fastqsanger.gz | |||
| SRR29098260_2.fastq.gz | Fastqsanger.gz | |||
| SRR29098261_1.fastq.gz | Fastqsanger.gz |
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Project description:We have identified and characterized two lysine (K) deacetylase inhibitors (DACi), CM-444 and CM-1758. These inhibitors demonstrate the ability to promote myeloid differentiation in all acute myeloid leukemia (AML) subtypes at low, non-cytotoxic doses, setting them apart from other commercially available histone deacetylase inhibitors (HDACi). Upon analysis of the acetylome following treatment with CM-444 and CM-1758, we observed modulation of non-histone proteins involved in the enhancer–promoter chromatin regulatory complex, including bromodomain proteins (BRDs). This acetylation is crucial for enhancing the expression of key transcription factors directly involved in the differentiation therapy induced by CM-444 and CM-1758 in AML. In summary, these compounds present promising potential as effective differentiation-based therapeutic agents across AML subtypes, offering a novel mechanism for the treatment of AML
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Project description:Novel epigenetic based differentiation therapy for Acute Myeloid Leukemia
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Project description:Despite the development of novel therapies for acute myeloid leukemia (AML), outcomes remain poor for most patients, and therapeutic improvements are an urgent unmet need. Although treatment regimens promoting differentiation have succeeded in the treatment of acute promyelocytic leukemia (APL), their role in other AML subtypes needs to be explored. Here we identified and characterized two lysine (K) deacetylase inhibitors (DACi), CM-444 and CM-1758, exhibiting higher capacity to promote myeloid differentiation in all AML subtypes at low non-cytotoxic doses than commercial HDACi. Analyzing the acetylome after CM-444 and CM-1758 treatment revealed modulation of non-histone proteins involved in the enhancer–promoter chromatin regulatory complex, including bromodomain proteins (BRDs). This acetylation was essential for enhancing the expression of key transcription factors directly involved in the differentiation therapy provided by CM-444/CM-1758 in AML. In summary, these compounds may represent effective differentiation-based therapeutic agents across AML subtypes with a novel mechanism for treatment of AML.
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Project description:Despite the development of novel therapies for acute myeloid leukemia (AML), outcomes remain poor for most patients, and therapeutic improvements are an urgent unmet need. Although treatment regimens promoting differentiation have succeeded in the treatment of acute promyelocytic leukemia (APL), their role in other AML subtypes needs to be explored. Here we identified and characterized two lysine (K) deacetylase inhibitors (DACi), CM-444 and CM-1758, exhibiting capacity to promote myeloid differentiation in all AML subtypes at low non-cytotoxic doses unlike other commercial HDACi. Analyzing the acetylome after CM-444 and CM-1758 treatment revealed modulation of non-histone proteins involved in the enhancer–promoter chromatin regulatory complex, including bromodomain proteins (BRDs). This acetylation was essential for enhancing the expression of key transcription factors directly involved in the differentiation therapy induced by CM-444/CM-1758 in AML. In summary, these compounds may represent effective differentiation-based therapeutic agents across AML subtypes with a novel mechanism for treatment of AML.
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Project description:Cure rates for patients with acute myeloid leukemia (AML) remain low despite ever-increasing dose intensity of cytotoxic therapy. In an effort to identify novel approaches to AML therapy, we recently reported a new method of chemical screening based on the modulation of a gene expression signature of interest. We applied this approach to the discovery of AML-differentiation-promoting compounds. Among the compounds inducing neutrophilic differentiation was DAPH1 (4,5-dianilinophthalimide), previously reported to inhibit epidermal growth factor receptor (EGFR) kinase activity. Here we report that the Food and Drug Administration (FDA)-approved EGFR inhibitor gefitinib similarly promotes the differentiation of AML cell lines and primary patient-derived AML blasts in vitro. Gefitinib induced differentiation based on morphologic assessment, nitro-blue tetrazolium reduction, cell-surface markers, genome-wide patterns of gene expression, and inhibition of proliferation at clinically achievable doses. Importantly, EGFR expression was not detected in AML cells, indicating that gefitinib functions through a previously unrecognized EGFR-independent mechanism. These studies indicate that clinical trials testing the efficacy of gefitinib in patients with AML are warranted. golub-00392 Assay Type: Gene Expression Provider: Affymetrix Array Designs: HG-U133A, HG-U133A_2 Organism: Homo sapiens (ncbitax) Material Types: cell, total_RNA, synthetic_RNA, organism_part, whole_organism*Cell Types: Disease States: Acute Myeloid Leukemia, Normal, Acute Myeloid Leukemia
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