Table 2.
Effect of mutation on aberrant methylation (taken from [67]). It is clear from this table that many of the downstream consequences in relation to development of AML are still unclear. Many of these cytogenetic mutations causing AML are rare and have only been observed in a few patients to date.
| Genetic alteration | Signature of DNA methylation patterns | Suggested mechanism of aberrant DNA methylation induction in AML |
|---|---|---|
| PML-RARa t(15;17) |
Accentuated hypermethylation and hypomethylation. | PML-RARa suggested to recruit DNMTs to binding site causing DNA hypermethylation. Secondary epigenetic dysregulation as PML-RARa binds to genomic regions of epigenetic modifiers including DNMT3A. |
| AML1/ETO t(8;21) |
Accentuated hypermethylation and hypomethylation. Though predominantly hypomethylation. |
Unclear mechanism AML1/ETO may recruit DNMT1 and HDAC1. Possibly works through secondary DNA methylation disruption of AML1-ETO target genes. |
| CBFb-MYH11 inv(16)— t(16;16) |
Predominantly hypomethylation. | Unclear mechanism. |
| TET2 mutations | Hypermethylation signature. | Mutated TET2 is impaired in its hydroxymethylation capacity. Unclear if DNA hypermethylated genes are direct TET2 target genes. |
| IDH1/2 mutations |
Pronounced genome wide hypermethylation signature. | Possibly via IDH (isocitrate dehydrogenase) mutations result in DNA hypermethylation via inhibition of α-ketoglutarate dependent dioxygenases (e.g., TET2). |
| DNMT3A mutations |
Genome-wide DNA hypomethylation signature: studies give mixed findings. | Mechanism of aberrant DNA methylation induction unclear. In vitro mechanism may be through loss of catalytic activity via R882H mutation. Unclear in vivo mechanism. |
| MLL-translocation -(11q23) | Pronounced DNA hypomethylation signature. | Unclear mechanism. |
| CEBPα mutations |
Two patterns of hypomethylated and hypermethylated sites depending on the detection method used. | Unclear mechanism. |
| RUNX1 mutations |
Discrete hypermethylation and hypomethylation signature. | Unclear mechanism. |
| NPM1 mutations |
Mixed hypermethylation and hypomethylation pattern. Strong hypomethylation in some studies. | Unclear mechanism. |