AMLs harboring DNMT3A-destabilizing variants show increased intratumor DNA methylation heterogeneity at bivalent chromatin domains

The mechanistic link between the complex mutational landscape of de novo methyltransferase DNMT3A and the pathology of acute myeloid leukemia (AML) has not been clearly elucidated so far. A recent discovery on the catalogue of DNMT3A-destabilizing mutations throughout the DNMT3A gene as well as the oligomerization-dependent catalytic property of DNMT3A prompted us to investigate the common effect of DNMT3A-destabilizing mutations (DNMT3A-INS) on the genomewide methylation patterns of AML cells. In this study, we describe the characteristics of DNMT3A-INS AML methylomes through the comprehensive computational analyses on three independent AML cohorts. As a result, we show that methylomes of DNMT3A-INS AMLs are considerably different from those of DNMT3A-R882 AMLs in that they exhibit both locally disordered DNA methylation states and increased across-cell DNA methylation heterogeneity in bivalent chromatin domains. This increased epigenetic heterogeneity was functionally associated with heterogeneous expression of membrane-associated factors shaping stem cell niche, implying the diversification of the modes of leukemic stem cell-niche interactions. We also present that the level of methylation disorder at bivalent domains predicts the response of AML cells to hypomethylating agents through cell line- and patient-level analyses, which supports that the survival of AML cells depends on stochastic DNA methylations at bivalent domains. Our work provides a novel mechanistic model suggesting the genomic origin of the aberrant epigenomic heterogeneity in disease conditions and underscores the clinical significance of the malignant increase of adaptive potentials of cell populations.