D9, a novel 3-Deazaneplanocin A (DZNep) analog, is efficacious in targeting acute myeloid leukemia (AML) (Sensitive vs Resistance)

ABSTRACT: We and others have previously reported that 3-Deazaneplanocin A (DZNep) is a histone methylation inhibitor that has a wide range anticancer effects in a variety of human cancers. Here, using acute myeloid leukemia as a model, we reported a less toxic analog of DZNep, named D9, that is shown to be efficacious in both cell lines and patient samples of AML. Gene expression analysis in a panel of AML cell lines treated with D9 identified a set of genes that is associated with D9 sensitivity and is implicated in multiple oncogenic signaling pathways. Moreover, we show that D9 is able to deplete the leukemia stem cells (LSC) and abolish chemotherapy-induced LSC enrichment, leading to dramatic elimination of AML cell survival and associated gene expression when combined with chemotherapy. Thus, D9 appears to be a robust epigenetic compound that may constitute a potential for AML therapy. We evaluated the overall effects of D9 on histone lysine methylations in AML cell lines and its relationship to apoptosis induction by D9. The results demonstrated that the both sensitive and resistant cell lines, treated with D9 for 48 and 72 hours, showed similar levels of suppression of histone lysine methylation. Thus, the differential sensitivities of AML cells to D9 is not due to its different ability to inhibit the bulk histone methylation but is more likely to be associated with the differential gene expression response to D9. To test this hypothesis, we treated three sensitive (MOLM-14, MV4-11 and TF-1) and three resistant (Mono-Mac-1, THP-1, and KG-1a) cell lines with D9 at 1 or 5 μM for 48 hours and performed Illumina BeadChip transcriptom profiling analysis. Significance Analysis of Microarrays (SAM) analysis shows that D9 treatment resulted in transcriptional changes of 547 genes, including 327 upregulated genes and 220 downregulated genes in sensitive cell lines but not in resistant cell lines.

ORGANISM(S): Homo sapiens

SUBMITTER: Xia Jiang 

PROVIDER: E-GEOD-59624 | biostudies-arrayexpress |

REPOSITORIES: biostudies-arrayexpress