The system is based on CRISPR-dCas9 fused with the catalytic domain of DNA methyltransferase 3A (DNMT3A
), an enzyme that is responsible for DNA methylation.
The mutations in AML involve epigenetic modifiers (TET2, IDH1/IDH2, DNMT3A
, ASXL1, KMT2A, EZH2), activated signaling pathway (FLT3, KRAS, NRAS, KIT), tumor suppressor genes (TP53, WT1), RNA splicing (SF3B1), nucleophosmin mutation (NPM1), and genes coding for transcription-differentiation (CEBPA, RUNX1) (Figure 1) (6-8).
Eight somatic mutations (STK11 c.291-1G>C, TP53 p.D281E, SMARCA4 p.E1542*, PCNT p.E1491D, INPP4B p.N228K, ALK p.S639R, DNMT3A
p.Y395C, and INPP4B p.T671S) were detected in tumor-peripheral blood paired genetic testing.
Four main variants of DNMTs are found in humans, namely DNMT1, DNMT3A
, DNMT3B, and DNMT3L, to mediate the methylation process.
The data suggest that one mutation in any of these pathways is sufficient for the pathogenesis of AML and that certain mutations common in AML (e.g., in DNMT3A
, NPM1, CEPBA, IDH1/2, and RUNX1) play a role in the initiation of AML similar to the fusion genes.
(31,32) The most commonly involved genes include DNMT3A
, TET2, and ASXL1; however, other frequently mutated genes include TP53, JAK2, SF3B1, GNB1, PPM1D, GNAS, and BCORL1.
The genomic methylation patterns in mammals that take place during embryogenesis involve overall three DNA methyltranferases DNMT1, DNMT3a
 In addition to regulating various cellular processes, miRNAs are epigenetic modulators by targeting mRNAs of epigenetic regulators including DNA methyltransferase 3 alpha (DNMT3A
), DNA methyltransferase 3 Beta (DNMT3B), polycomb mRNAs, EZH2 (as shown above), BMI1 and HDAC4.
El consumo excesivo de alcohol se caracteriza por hipometilacion global del ADN (Schernhammer et al, 2010) e hipermetilacion de ciertos genes, como por ejemplo, el mARN involucrado en la regulacion de DNMT3a
y DNMT3b (Bonsch et al., 2006).
Differential methylation in CN-AML preferentially targets non-CGI regions and is dictated by DNMT3A
mutational status and associated with predominant hypomethylation of HOX genes.
and DNMT3al expression levels have been shown to be increased significantly in M2 compared to M1 macrophages, and this is associated with AMPK signaling .