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Combined epigenetic and metabolic treatments overcome differentiation blockade in acute myeloid leukemia

ABSTRACT: This SuperSeries is composed of the SubSeries listed below.

ORGANISM(S): Mus musculus

PROVIDER: GSE162398 | GEO | 2020/12/04

REPOSITORIES: GEO

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Combined epigenetic and metabolic treatments overcome differentiation blockade in acute myeloid leukemia.

Project description:A hallmark of acute myeloid leukemia (AML) is the inability of self-renewing malignant cells to mature into a non-dividing terminally differentiated state. This differentiation block has been linked to dysregulation of multiple cellular processes, including transcriptional, chromatin, and metabolic regulation. The transcription factor HOXA9 and the histone demethylase LSD1 are examples of such regulators that promote differentiation blockade in AML. To identify metabolic targets that interact with LSD1 inhibition to promote myeloid maturation, we screened a small molecule library to identify druggable substrates. We found that differentiation caused by LSD1 inhibition is enhanced by combined perturbation of purine nucleotide salvage and de novo lipogenesis pathways, and identified multiple lines of evidence to support the specificity of these pathways and suggest a potential basis of how perturbation of these pathways may interact synergistically to promote myeloid differentiation. In sum, these findings suggest potential drug combination strategies in the treatment of AML.

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Combined epigenetic and metabolic treatments overcome differentiation blockade in acute myeloid leukemia [ATAC-Seq]

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Project description:A hallmark of acute myeloid leukemia (AML) is the inability of self-renewing malignant cells to mature into a non-dividing terminally differentiated state. To better understand how chromatin factors such as LSD1 interact with metabolic pathways to support the differentiation blockade, we screened a small molecule library to identify druggable substrates that promote myeloid maturation. We found that differentiation caused by LSD1 inhibition is enhanced by combinatorial perturbation of purine nucleotide salvage and de novo lipogenesis pathways. We used RNA-seq to determine whether the drug combination induces gene expression changes consistent with myeloid differentiation.

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Combined epigenetic and metabolic treatments overcome differentiation blockade in acute myeloid leukemia

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Combined epigenetic and metabolic treatments overcome differentiation blockade in acute myeloid leukemia [ATAC-Seq]

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Novel epigenetic based differentiation therapy for Acute Myeloid Leukemia

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:Acute myeloid leukemia (AML) is a genetically heterogeneous disease. Certain cytogenetic and molecular genetic mutations are recognized to have an impact on prognosis, leading to their inclusion in some prognostic stratification systems. Recently, the advent of high-throughput whole genome or exome sequencing has led to the identification of several novel recurrent mutations in AML, a number of which have been found to involve genes concerned with epigenetic regulation. These genes include in particular DNMT3A, TET2, and IDH1/2, involved with regulation of DNA methylation, and EZH2 and ASXL-1, which are implicated in regulation of histones. However, the precise mechanisms linking these genes to AML pathogenesis have yet to be fully elucidated as has their respective prognostic relevance. As massively parallel DNA sequencing becomes increasingly accessible for patients, there is a need for clarification of the clinical implications of these mutations. This review examines the literature surrounding the biology of these epigenetic modifying genes with regard to leukemogenesis and their clinical and prognostic relevance in AML when mutated.

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