Identification of DNA methylation prognostic signature of acute myelocytic leukemia

Zhang, Haiguo; Song, Guodong; Song, Guanbo; Li, Ruolei; Gao, Min; Ye, Ling; Zhang, Chengfang

doi:10.1371/journal.pone.0199689

Cited by 9 publications

(11 citation statements)

References 75 publications

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“…4). Among the dysregulated FOXK1/K2 targets by mutant ASXL1 are multiple tumor suppressors: VHL mutations and promoter hypermethylation play a crucial role in the development of AML (Labno-Kirszniok et al, 2013;Gossage et al, 2015;Moura et al, 2018); SOCS1 and SOCS2 are associated with dysregulation of cell growth, cancer-associated inflammation, and cell death induced by multiple cytokines and hormones (Duncan et al, 2017;Jiang et al, 2017); TXNIP plays an important role in glucose uptake and redox homeostasis (Waldhart et al, 2017). Phenotypically, mutant ASXL1 impairs the BAP1-ASXL1-FOXK1/K2 transcriptional nexus and downregulates TXNIP, VHL, and SOCS1/2, and consequently promotes glucose metabolism and enhances oncogenic HIF-1α and JAK-STAT3 signaling pathways known to be altered in hematological malignancies.…”

Section: Discussionmentioning

confidence: 99%

“…Numerous studies have established the oncogenic roles of VHL/HIF-1α and SOCS/JAK-STAT pathways in regulating leukemia cell growth and hematological malignancies (Labno-Kirszniok et al, 2013;Moura et al, 2018). We found that C-terminally truncated ASXL1 mutant mildly increased the cellular susceptibility to STAT3 inhibitor, with the IC 50 for C188-9 being 7.9 ± 0.72 μmol/L and 11.84 ± 1.31 μmol/L in ASXL1 +/N590 and ASXL1 +/− cells, respectively (Fig.…”

Section: Tumor-derived Asxl1 Mutants Promote Leukemia Cell Growth Thrmentioning

confidence: 99%

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Tumor-derived neomorphic mutations in ASXL1 impairs the BAP1-ASXL1-FOXK1/K2 transcription network

et al. 2020

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Additional sex combs-like 1 (ASXL1) interacts with BRCA1-associated protein 1 (BAP1) deubiquitinase to oppose the polycomb repressive complex 1 (PRC1)mediated histone H2A ubiquitylation. Germline BAP1 mutations are found in a spectrum of human malignancies, while ASXL1 mutations recurrently occur in myeloid neoplasm and are associated with poor prognosis. Nearly all ASXL1 mutations are heterozygous frameshift or nonsense mutations in the middle or to a less extent the C-terminal region, resulting in the production of C-terminally truncated mutant ASXL1 proteins. How ASXL1 regulates specific target genes and how the C-terminal truncation of ASXL1 promotes leukemogenesis are unclear. Here, we report that ASXL1 interacts with forkhead transcription factors FOXK1 and FOXK2 to regulate a subset of FOXK1/K2 target genes. We show that the C-terminally truncated mutant ASXL1 proteins are expressed at much higher levels than the wild-type protein in ASXL1 heterozygous leukemia cells, and lose the ability to interact with FOXK1/K2. Specific deletion of the mutant allele eliminates the expression of C-terminally truncated ASXL1 and increases the association of wild-type ASXL1 with BAP1, thereby restoring the expression of BAP1-ASXL1-FOXK1/K2 target genes,

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Section: Discussionmentioning

confidence: 99%

Section: Tumor-derived Asxl1 Mutants Promote Leukemia Cell Growth Thrmentioning

confidence: 99%

Tumor-derived neomorphic mutations in ASXL1 impairs the BAP1-ASXL1-FOXK1/K2 transcription network

et al. 2020

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“…GABBR1 has been introduced as a survival associated marker for AML 32 . Excessive signal transduction through GABBR1 triggers growth and migration of cancer cells 32 . These ndings support our data showing the association of increased expression of GABBR1 and chemoresistance in AML samples.…”

Section: Discussionmentioning

confidence: 99%

“…6b) 31 . GABBR1 has been introduced as a survival associated marker for AML 32 . Excessive signal transduction through GABBR1 triggers growth and migration of cancer cells 32 .…”

Section: Discussionmentioning

confidence: 99%

Suppression of JNK Pathway as a Novel Regulator of Chemo-Resistance in AML: A Meta-Analysis of Gene Signatures and Key Pathways

Modarres¹,

Farsani²,

Nekouie³

et al. 2021

Preprint

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The pathways and robust deregulated gene signatures involved in AML chemo-resistance are not fully understood. Multiple subgroups of AMLs which are under treatment of various regimens seem to have similar regulatory gene(s) or pathway(s) related to their chemo-resistance phenotype. In this study using gene set enrichment approach, deregulated genes and pathways associated with relapse after chemotherapy were investigated in AML samples. Five AML libraries compiled from GEO and ArrayExpress repositories were used to identify significantly differentially expressed genes between chemo-resistance and chemo-sensitive groups. Functional and pathway enrichment analysis of differentially expressed genes was performed to assess molecular mechanisms related to AML chemotherapeutic resistance. A total of 34 genes were selected to be differentially expressed in chemo-resistance compared to chemo-sensitive group. Among these genes, c-Jun, AKT3, ARAP3, GABBR1, PELI2 and SORT1 are involved in neurotrophin, estrogen, cAMP and Toll-like receptor signaling pathways. All these pathways are located upstream and regulate JNK signaling pathway which functions as a key regulator of cellular apoptosis. Our expression data are in favor of suppression of JNK pathway, which could induce pro-apoptotic gene expression as well as down regulation of survival factors, suggesting this pathway as a novel key regulator of drug-resistance development in AML.

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“…DNA methylation changes in the peripheral blood have been considered to have great potential as a source of locus-specific biomarkers that can be used for the early detection and monitoring of environmental pollution [6, 7]. This promise is considerable and has been fulfilled by the use of alterations of DNA methylation in populations exposed to pollutants such as cadmium[8], and polycyclic aromatic hydrocarbon[9]; however, a new and more reliable, repaid and sensitive method for promoter methylation analyses in clinical samples is needed.…”

Section: Introductionmentioning

confidence: 99%

The prevalence and persistence of aberrant promoter DNA methylation in benzene-exposed Chinese workers

et al. 2019

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Aberrant DNA methylation patterns are common in cancers and environmental pollutant exposed subjects. Up to date, few studies have examined the aberrant DNA methylation patterns in benzene exposed workers. We recruited 141 benzene-exposed workers, including 83 benzene-exposed workers from a shoe factory in Wenzhou and 58 workers from a painting workshop in Wuhu, 35 workers in Wuhu were followed from 2009 to 2013, and 48 indoor workers as controls from Wenzhou. We used high-resolution melting (HRM) to quantitate human samples of DNA methylation in long interspersed nuclear element-1 (LINE-1), (6)-methylguanine-DNA methyltransferase (MGMT), and DNA mismatch repair gene human mutator L homologue 1 (hMLH1). AML-5 cells were treated with benzoquinone (BQ) and hydroquinone (HQ), and the promoter methylation of MGMT and hMLH1 was detected using the bisulfite sequencing PCR method. The degree of LINE-1 methylation in benzene-exposed workers was significantly lower than that of the controls ( p <0.001), and the degree of MGMT ( p <0.001) and hMLH1 ( p = 0.01) methylation was significantly higher than that of the controls. The in vitro study validated the aberrant hypermethylation of hMLH1 after treatment with BQ. Among the cohort workers who were followed from 2009 to 2013, the LINE1 methylation elevated in 2013 than 2009 ( p = 0.004), and premotor methylation in hMLH1 reduced in 2013 than 2009 ( p = 0.045) with the reduction of the benzene exposure. This study provides evidence that benzene exposure can induce LINE-1 hypomethylation and DNA repair gene hypermethylation.

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Identification of DNA methylation prognostic signature of acute myelocytic leukemia

Cited by 9 publications

References 75 publications

Tumor-derived neomorphic mutations in ASXL1 impairs the BAP1-ASXL1-FOXK1/K2 transcription network

Tumor-derived neomorphic mutations in ASXL1 impairs the BAP1-ASXL1-FOXK1/K2 transcription network

Suppression of JNK Pathway as a Novel Regulator of Chemo-Resistance in AML: A Meta-Analysis of Gene Signatures and Key Pathways

The prevalence and persistence of aberrant promoter DNA methylation in benzene-exposed Chinese workers

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