Chronic myelomonocytic leukemia (CMML) is an aggressive myeloid neoplasm for which currently no effective therapies exist. Particularly patients with truncating mutations in ASXL1 do not fare well and the development of novel therapeutic approaches remains an unmet clinical need.1 The chromatin modifier ASXL1 is involved in the maintenance of balanced gene expression of leukemogenic driver genes such as posterior HOXA cluster genes. Mechanistic studies suggest that ASXL1 has a complex interactome and that truncating ASXL1 mutations recruit several effectors to alter the epigenome through histone modifications, increases in chromatin accessibility, and remodeling of enhancers.2-4 ASXL1-mutant CMML represents a high-risk disease subtype characterized by an overexpression of leukemogenic driver genes that promote disease proliferation, therapeutic resistance, and transformation to acute myeloid leukemia. In this study, we interrogated the genome, transcriptome, and epigenome of patients with ASXL1-mutant CMML to learn more about the epigenetic determinants of leukemogenic gene expression in this patient population.
By comparing CMML patients with and without ASXL1 mutations, we identified several effects that ASXL1 mutations have on the epigenome and transcriptome of malignant monocytes in the bone marrow. We observed widespread chromatin remodeling and characteristic changes in gene expression that are consistent with the known proliferative disease phenotype (e.g. the overexpression of mitotic kinases). To understand how these changes in gene expression are supported by the epigenome, we interrogated histone modifications, DNA methylation, and DNA accessibility. We observed a strong effect of histone modifications in promoter regions and distal enhancers on the expression of important leukemogenic driver genes. In promoter regions of many overexpressed genes, a transition from poised and inactive chromatin states to active chromatin states was observed. This was mainly driven by increases in histone 3 lysine 27 acetylation (H3K27ac) and decreases in histone 3 lysine 27 trimethylation (H3K27me3). Importantly, these chromatin state transitions were quite heterogenous across the spectrum of overexpressed genes and did not necessarily reflect the global trends observed across the entire epigenome.
Overall, this study supports the notion that genotype-specific distal enhancers have a specific repertoire of transcription factors binding to them, strongly associate with the overexpression of important leukemogenic driver genes in their proximity, and may be attractive therapeutic targets for novel epigenetic small molecule drugs. These ASXL1-mutant-specific distal enhancers and their interacting transcription factors may represent sufficiently lineage- and genotype-specific therapeutic targets to allow the development of safe and effective individualized therapies for patients with ASXL1-mutant CMML.
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