Epigenetic Regulators in the Development, Maintenance, and Therapeutic Targeting of Acute Myeloid Leukemia

Sun, Younguk; Chen, Bo‐Rui; Deshpande, Aniruddha J.

doi:10.3389/fonc.2018.00041

Cited by 48 publications

(48 citation statements)

References 191 publications

(156 reference statements)

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“…AML, the most common form of acute leukemias in adults, is a clonal malignant hematologic disorder characterized by impaired hematopoiesis and concurrent buildup of immature myeloid blasts [18,39]. The epigenetic characterization of AML decodes aberrant mechanisms inducing differential gene expression relevant to the malignant makeover [1,40]. Of the many ways in which epigenetic deregulations are manifested in leukemogenesis, DNA methylation and histone deacetylation are at the forefront [1,3].…”

Section: Discussionmentioning

confidence: 99%

Adjuvant Epigenetic Therapy of Decitabine and Suberoylanilide Hydroxamic Acid Exerts Anti-Neoplastic Effects in Acute Myeloid Leukemia Cells

Najem

Khawaja

Hodroj

et al. 2019

Cells

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Atypical epigenetic processes including histone acetylation and DNA methylation have been identified as a fundamental theme in hematologic malignancies. Such mechanisms modify gene expression and prompt, in part at least, the initiation and progression of several malignancies including acute myeloid leukemia. In the current study we determined the effects of treating KG-1 and U937 acute myeloid leukemia (AML) cells, in vitro, with the HDAC inhibitor, suberoylanilide hydroxamic acid (SAHA), or with a DNMT inhibitor, decitabine (DAC), or their combination, on cell proliferation, cell cycle progression, apoptosis, and expression of apoptosis-related proteins. Each of SAHA and DAC attenuated cell proliferation and induced cell cycle arrest and apoptotic cell death of KG-1 and U937 cell lines. Besides, their sequential combination improved the obtained anti-neoplastic effect: significant augmentation of growth inhibition and apoptosis induction as compared to cells treated with either drug alone. This effect was featured by the upregulated expression of Bax, cytochrome c1, p21, and cleaved caspases 8, 9, and 3, signifying the activation of both the intrinsic and extrinsic pathways of apoptosis. The sequential combination of SAHA and DAC causes a profound antitumorigenic effect in AML cell lines by inducing the expression of tumor suppressor genes. feature of malignancy. Promoter CpG island hypermethylation of tumor suppressor genes, as mediated by DNA methyltransferase enzymes (DNMTs), is well-reported to associate with a closed chromatin structure and potent transcriptional silencing that inactivates key cellular pathways like DNA damage repair and apoptosis [10,11].The two epigenetic mechanisms are functionally interdependent [12]. DNMTs with several DNA binding factors associate with HDACs to form corepressor complexes that alter chromatin architecture and, subsequently, the transcription of putative target genes [13,14]. Trichostatin A, a histone deacetylase inhibitor, induced DNA demethylation in human cancer cell lines [15], and the use of 5-azacytidine, a demethylating agent, mediated an increase in H4 acetylation [16], therefore providing evidence for an integrated crosstalk between the two epigenetic mechanisms.Dysregulated epigenetic mechanisms are central in the pathogenesis of acute myeloid leukemia (AML), the most common type of acute leukemia in adults with poor prognosis despite induction therapy [17][18][19]. Epigenetic shifts impair the differentiation of myeloid progenitors and promote their uncontrolled clonal proliferation leading to bone marrow failure [20].Unique DNA methylation profiles were reported in AML patient samples. Many genes were found to be differentially hypermethylated and repressed [21,22]. AML blasts also exhibited significant modifications in histone acetylation levels at more than 1000 genomic loci compared with progenitor cells with fundamental promoter regions being hypoacetylated in AML compared with progenitor cells [23].The major role of epigenetics in myeloid leukemogenesi...

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Section: Discussionmentioning

confidence: 99%

Adjuvant Epigenetic Therapy of Decitabine and Suberoylanilide Hydroxamic Acid Exerts Anti-Neoplastic Effects in Acute Myeloid Leukemia Cells

Najem

Khawaja

Hodroj

et al. 2019

Cells

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“…AML is a clonal malignancy that results from genetic and epigenetic abnormalities which leads to uncontrolled proliferation and impaired differentiation of hematopoietic stem and progenitor cells [9][10][11]. Cytogenetic analysis for the detection of chromosomal abnormalities was the first prognostication tool in AML and still remains the backbone of current AML genomic classification [12].…”

Section: Acute Myeloid Leukemia (Aml)mentioning

confidence: 99%

The Role of MYC and PP2A in the Initiation and Progression of Myeloid Leukemias

Pippa

Odero

2020

Cells

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The MYC transcription factor is one of the best characterized PP2A substrates. Deregulation of the MYC oncogene, along with inactivation of PP2A, are two frequent events in cancer. Both proteins are essential regulators of cell proliferation, apoptosis, and differentiation, and they, directly and indirectly, regulate each other’s activity. Studies in cancer suggest that targeting the MYC/PP2A network is an achievable strategy for the clinic. Here, we focus on and discuss the role of MYC and PP2A in myeloid leukemias.

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“…The coordinated action of transcriptional regulators and epigenetic modifiers regulates the path a cell takes as it transcends the hematopoietic hierarchy, with terminal differentiation requiring silencing of the multilineage transcriptome and activation of the transcriptional program governing terminal differentiation. Highlighting this fact, mutations that disrupt epigenetic or transcriptional regulation in multipotent hematopoietic stem and progenitor cells can result in leukemia, myelodysplastic syndromes, and other types of bone marrow failure [4][5][6][7].…”

Section: Introductionmentioning

confidence: 99%

The histone methyltransferase Setd8 alters the chromatin landscape and regulates the expression of key transcription factors during erythroid differentiation

Myers

Couch

Murphy

et al. 2020

Epigenetics & Chromatin

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Background: SETD8 is the sole methyltransferase capable of mono-methylating histone H4, lysine 20. SETD8 and H4K20me1 play a role in a number of essential biologic processes, including cell cycle progression, establishment of higher order chromatin structure, and transcriptional regulation. SETD8 is highly expressed in erythroid cells and erythroid deletion of Setd8 is embryonic lethal by embryonic day 11.5 (E11.5) due to profound anemia, suggesting that it has an erythroid-specific function. The function of SETD8 in the hemopoietic system is poorly understood. The goal of our study was to gain insights into the function of SETD8 during erythroid differentiation. Results:We performed ATAC-seq (assay for transposase-accessible chromatin) on sorted populations of E10.5 Setd8 mutant and control erythroblasts. Accessibility profiles were integrated with expression changes and a mark of heterochromatin (H3K27me3) performed in wild-type E10.5 erythroblasts to further understand the role of SETD8 in erythropoiesis. Data integration identified regions of greater chromatin accessibility in Setd8 mutant cells that colocated with H3K27me3 in wild-type E10.5 erythroblasts suggesting that these regions, and their associated genes, are repressed during normal erythropoiesis. The majority of these more accessible regions were located in promoters and they frequently co-located with the NFY complex. Pathway analysis of genes identified through data integration revealed stemness-related pathways. Among those genes were multiple transcriptional regulators active in multipotent progenitors, but repressed during erythroid differentiation including Hhex, Hlx, and Gata2. Consistent with a role for SETD8 in erythroid specification, SETD8 expression is up-regulated upon erythroid commitment, and Setd8 disruption impairs erythroid colony forming ability. Conclusion:Taken together, our results suggest that SETD8 is an important regulator of the chromatin landscape during erythroid differentiation, particularly at promoters. Our results also identify a novel role for Setd8 in the establishment of appropriate patterns of lineage-restricted gene expression during erythroid differentiation.

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Epigenetic Regulators in the Development, Maintenance, and Therapeutic Targeting of Acute Myeloid Leukemia

Cited by 48 publications

References 191 publications

Adjuvant Epigenetic Therapy of Decitabine and Suberoylanilide Hydroxamic Acid Exerts Anti-Neoplastic Effects in Acute Myeloid Leukemia Cells

Adjuvant Epigenetic Therapy of Decitabine and Suberoylanilide Hydroxamic Acid Exerts Anti-Neoplastic Effects in Acute Myeloid Leukemia Cells

The Role of MYC and PP2A in the Initiation and Progression of Myeloid Leukemias

The histone methyltransferase Setd8 alters the chromatin landscape and regulates the expression of key transcription factors during erythroid differentiation

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