A recent study published in Genes & Diseases by researchers from University of Arkansas for Medical Sciences, Cantata Bio, Seattle Children's Research Institute and Fred Hutchinson Cancer Center uses an integrated multi-omics approach to uncover how the C/G fusion extensively rewires DNA methylation and enhancer activity, producing a leukemia-specific epigenetic landscape.
Genome-wide methylation profiling across C/G+ patient samples and C/G+ cell lines revealed a distinct global hypermethylation signature, affecting more than 90,000 CpG sites and involving over 20,000 genes. Remarkably, many up-regulated C/G-restricted genes showed promoter hypermethylation yet retained open chromatin states enriched with H3K27ac—highlighting a non-canonical mechanism where hypermethylation supports, rather than represses, transcriptional activation. These genes include key adhesion molecules, TGFβ/Wnt signaling components, and immunotherapeutic targets such as HPSE2, CMTM5, and GP1BA.
By integrating chromatin-state modeling with promoter capture Hi-C, the study demonstrates that C/G+ leukemia cells undergo extensive de novo promoter–enhancer looping, often independent of CTCF binding. These loops frequently originate at hypermethylated enhancer regions, suggesting that enhancer methylation helps stabilize oncogenic chromatin interactions. This structural rewiring aligns with major transcriptional programs that support leukemic proliferation, adhesion, and lineage plasticity.
A major highlight of the study is the identification of DNMT3B as a critical downstream effector of the C/G fusion. CUT&RUN mapping showed direct binding of C/G at the DNMT3B promoter, accompanied by elevated DNMT3B expression in C/G+ samples. Functional knockout of DNMT3B led to extensive hypomethylation—especially at enhancer-bound regions—and down-regulation of C/G-restricted oncogenes. Importantly, DNMT3B loss significantly enhanced sensitivity to the BCL-2 inhibitor venetoclax, overcoming the apoptotic resistance characteristic of this leukemia subtype, and highlighting DNMT3B-dependent enhancer regulation as a therapeutic vulnerability.
In summary, this study shows that the CBFA2T3-GLIS2 fusion reshapes the epigenome through enhancer-associated DNA methylation and DNMT3B-driven chromatin remodeling, creating a transcriptional program that fuels leukemic growth. These findings suggest that targeting DNMT3B-mediated epigenetic circuits may offer a promising therapeutic strategy for this high-risk pediatric leukemia subtype.
Genes & Diseases