Epigenetic reprogramming
Cancer changes not just its genes but how they are read: chemical tags on DNA and histones silence guardians and awaken growth programmes. Unlike mutations, these changes are reversible, which is the hope behind epigenetic drugs.
DNA methylation (DNMT1/3A, TET2, IDH-driven hypermethylation), histone marks (EZH2/H3K27me3, KMT2 family, H3K27M in glioma, NSD2 in myeloma), chromatin readers (BET proteins), and remodelling (SWI/SNF) are all mutated or hijacked. 'Non-mutational epigenetic reprogramming' is a 2022 hallmark: drug-tolerant persister states arise without new mutations. Approved: azacitidine/decitabine (MDS/AML), HDAC inhibitors (T-cell lymphoma), EZH2 (tazemetostat, withdrawn 2026), IDH inhibitors, menin inhibitors (KMT2A/NPM1 leukaemia). Solid tumour activity remains modest; combinations to re-express antigens or hormone receptors are the current bet. Methylation classifiers diagnose brain tumours and underlie cfDNA cancer detection.
In one picture
The genome is the book; epigenetics is the highlighting and the pages stapled shut. Cancer staples shut the safety chapters and highlights the growth chapters. Epigenetic drugs pull staples.
Diagram
top- Hypomethylating agents (azacitidine, decitabine) with venetoclax in AML
- Menin inhibitors (revumenib, ziftomenib) in KMT2A/NPM1 leukaemia
- IDH inhibitors reverse 2-HG hypermethylation
- HDAC, BET, LSD1 inhibitors mostly in trials; epigenetic priming for immunotherapy
Notes
top- Leading programmes: Baylin (Johns Hopkins, DNA methylation); Pfister (DKFZ, methylation classification); Armstrong (Dana-Farber, menin/KMT2A); Allis legacy (Rockefeller, histone code).