Epigenetic targeting and personalized approaches for AML

Roboz, Gail J.

doi:10.1182/asheducation-2014.1.44

Cited by 14 publications

(8 citation statements)

References 56 publications

(55 reference statements)

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“…4 ) [ 30 ]. Based on mechanism of action, genes involved in signal transduction ( FLT3 , CSF3R , KIT , NRAS , PTPN11 , CBL and JAK2 ) and DNA methylation ( DNMT3A , TET2 , IDH1 and IDH2 ) were the most frequent mutated groups, accounting for 24 (31 %) and 18 (23 %) out of 77 detectable mutations [ 31 ].…”

Section: Resultsmentioning

confidence: 99%

Clinical evaluation of panel testing by next-generation sequencing (NGS) for gene mutations in myeloid neoplasms

Au¹,

Wa²,

Ho³

et al. 2016

Diagn Pathol

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BackgroundGenomic techniques in recent years have allowed the identification of many mutated genes important in the pathogenesis of acute myeloid leukemia (AML). Together with cytogenetic aberrations, these gene mutations are powerful prognostic markers in AML and can be used to guide patient management, for example selection of optimal post-remission therapy. The mutated genes also hold promise as therapeutic targets themselves. We evaluated the applicability of a gene panel for the detection of AML mutations in a diagnostic molecular pathology laboratory.MethodsFifty patient samples comprising 46 AML and 4 other myeloid neoplasms were accrued for the study. They consisted of 19 males and 31 females at a median age of 60 years (range: 18–88 years). A total of 54 genes (full coding exons of 15 genes and exonic hotspots of 39 genes) were targeted by 568 amplicons that ranged from 225 to 275 bp. The combined coverage was 141 kb in sequence length. Amplicon libraries were prepared by TruSight myeloid sequencing panel (Illumina, CA) and paired-end sequencing runs were performed on a MiSeq (Illumina) genome sequencer. Sequences obtained were analyzed by in-house bioinformatics pipeline, namely BWA-MEM, Samtools, GATK, Pindel, Ensembl Variant Effect Predictor and a novel algorithm ITDseek.ResultsThe mean count of sequencing reads obtained per sample was 3.81 million and the mean sequencing depth was over 3000X. Seventy-seven mutations in 24 genes were detected in 37 of 50 samples (74 %). On average, 2 mutations (range 1–5) were detected per positive sample. TP53 gene mutations were found in 3 out of 4 patients with complex and unfavorable cytogenetics. Comparing NGS results with that of conventional molecular testing showed a concordance rate of 95.5 %. After further resolution and application of a novel bioinformatics algorithm ITDseek to aid the detection of FLT3 internal tandem duplication (ITD), the concordance rate was revised to 98.2 %.ConclusionsGene panel testing by NGS approach was applicable for sensitive and accurate detection of actionable AML gene mutations in the clinical laboratory to individualize patient management. A novel algorithm ITDseek was presented that improved the detection of FLT3-ITD of varying length, position and at low allelic burden.

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Section: Resultsmentioning

confidence: 99%

Clinical evaluation of panel testing by next-generation sequencing (NGS) for gene mutations in myeloid neoplasms

Au¹,

Wa²,

Ho³

et al. 2016

Diagn Pathol

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“…These findings have emphasized the potential of using epigenetically targeted therapies for the treatment of AML. Indeed, the DNMT inhibitors 5-azacitidine and 5-aza-2′deoxycytidine (decitabine) are effective agents in the treatment of patients with myelodysplastic syndromes and AML [13]. …”

Section: Introductionmentioning

confidence: 99%

MUC1-C induces DNA methyltransferase 1 and represses tumor suppressor genes in acute myeloid leukemia

et al. 2016

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Aberrant DNA methylation is a hallmark of acute myeloid leukemia (AML); however, the regulation of DNA methyltransferase 1 (DNMT1), which is responsible for maintenance of DNA methylation patterns, has largely remained elusive. MUC1-C is a transmembrane oncoprotein that is aberrantly expressed in AML stem-like cells. The present studies demonstrate that targeting MUC1-C with silencing or a pharmacologic inhibitor GO-203 suppresses DNMT1 expression. In addition, MUC1 expression positively correlates with that of DNMT1 in primary AML cells, particularly the CD34+/CD38− population. The mechanistic basis for this relationship is supported by the demonstration that MUC1-C activates the NF-κB p65 pathway, promotes occupancy of the MUC1-C/NF-κB complex on the DNMT1 promoter and drives DNMT1 transcription. We also show that targeting MUC1-C substantially reduces gene promoter-specific DNA methylation, and derepresses expression of tumor suppressor genes, including CDH1, PTEN and BRCA1. In support of these results, we demonstrate that combining GO-203 with the DNMT1 inhibitor decitabine is highly effective in reducing DNMT1 levels and decreasing AML cell survival. These findings indicate that (i) MUC1-C is an attractive target for the epigentic reprogramming of AML cells, and (ii) targeting MUC1-C in combination with decitabine is a potentially effective clinical approach for the treatment of AML.

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“…We demonstrate the utility of our method in AML using two independent genome-wide methylation datasets (see Figure 1). AML is the ideal case-study for our methodology, as recent work has shown that the AML epigenome evolves independently of mutational burden, and, furthermore, patients with AML respond well to DNA demethylating agents (also known as "epigenetic drugs") [13][14][15][16] . Using our pipeline, we recover significance for the most commonly used AML medication, cytarabine, as well as three other candidates with ongoing preclinical research in the AML space.…”

Section: Introductionmentioning

confidence: 99%