Abstract
Acute promyelocytic leukemia (APL) is characterized by a unique chromosome translocation t(15;17)(q24;q21), which leads to the PML/RARA gene fusion formation. However, it is acknowledged that this rearrangement alone is not able to induce the whole leukemic phenotype. In addition, epigenetic processes, such as DNA methylation, may play a crucial role in leukemia pathogenesis. DNA methylation, catalyzed by DNA methyltransferases (DNMTs), involves the covalent transfer of a methyl group (-CH3) to the fifth carbon of the cytosine ring in the CpG dinucleotide and results in the formation of 5-methylcytosine (5-mC). The aberrant gene promoter methylation can be an alternative mechanism of tumor suppressor gene inactivation. Understanding cancer epigenetics and its pivotal role in oncogenesis, can offer us not only attractive targets for epigenetic treatment but can also provide powerful tools in monitoring the disease and estimating the prognosis. Several genes of interest, such as RARA, RARB, p15, p16, have been studied in APL and their methylation status was correlated with potential diagnostic and prognostic significance. In the present manuscript we comprehensively examine the current knowledge regarding DNA methylation in APL pathogenesis. We also discuss the perspectives of using the DNA methylation patterns as reliable biomarkers for measurable residual disease (MRD) monitoring and as a predictor of relapse. This work also highlights the possibility of detecting aberrant methylation profiles of circulating tumor DNA (ctDNA) through liquid biopsies, using the conventional methods, such as methylation-specific polymerase chain reaction (MS-PCR), sequencing methods, but also revolutionary methods, such as surface-enhanced Raman spectroscopy (SERS).
Highlights
ON DNA METHYLATIONRealizing that all cells in an organism are derived from a single cell and that they share an almost identical genetic information has left open a crucial question: what is the molecular substrate accounting for the differences between cell types
The results suggested that isocitrate dehydrogenase (IDH) mutation results in the upregulation of CCAAT/enhancer binding protein α (CEBPα), which is a key regulatory switch enough for induction of differentiation toward the granulocyte lineage (32, 33)
Scaglioni et al report up-regulation of Birc1e (IAP inhibitor that counteracts cell death), Sept[9], and angiopoietin-like 4. All this gene alteration implies that 5-Azacytidine, through its epigenetic modifications, can promote leukemogenesis (68), which is surprising given the fact that according to previous studies, promyelocytic leukemia (PML)/retinoic acid receptor alpha (RARA)-induced hypermethylation and gene silencing is an important mechanism in acute promyelocytic leukemia (APL) pathogenesis (68)
Summary
Realizing that all cells in an organism are derived from a single cell (the zygote) and that they share an almost identical genetic information has left open a crucial question: what is the molecular substrate accounting for the differences between cell types. DNA methylation inhibits transcription via DNMTs, which recruit H3K9 histone methyltransferases and histone deacetylases as well as via 5mC readers possessing methyl-CpG-binding domains (MBDs) (17). This is how a repressive chromatin structure is produced. This close cooperation between DNA methylation and various epigenetic changes establishes the solid maintenance of gene expression changes during cell division and differentiation (7). Subsequent studies demonstrated that the following mechanism takes place: neomorphic IDH mutations confers a novel function to the FIGURE 1 | Methylation of the carbon 5 position of cytosine is catalyzed by DNA methyltransferases (DNMTs). The results suggested that IDH mutation results in the upregulation of CCAAT/enhancer binding protein α (CEBPα), which is a key regulatory switch enough for induction of differentiation toward the granulocyte lineage (32, 33)
Sign-in/Register to view highlights & summary Talk to us
Join us for a 30 min session where you can share your feedback and ask us any queries you have
Schedule a callDisclaimer: All third-party content on this website/platform is and will remain the property of their respective owners and is provided on "as is" basis without any warranties, express or implied. Use of third-party content does not indicate any affiliation, sponsorship with or endorsement by them. Any references to third-party content is to identify the corresponding services and shall be considered fair use under The CopyrightLaw.
