ASXL1 mutations that cause Bohring Opitz Syndrome (BOS) or acute myeloid leukemia share epigenomic and transcriptomic signatures

ASXL1 (Additional sex combs-like 1) plays key roles in epigenetic regulation of early developmental gene expression. De novo and truncating mutations of ASXL1 cause Bohring-Opitz Syndrome (BOS, OMIM #605039), a rare genetic disorder characterized by multiple congenital anomalies including: profound intellectual disability, seizures, heart defects, long and thick hair, and severe skeletal defects giving rise to ‘BOS posture’. These same BOS-causing ASXL1 mutations are also high-prevalence somatic driver mutations in acute myeloid leukemia (AML). We utilize primary cells from BOS patients (n = 18) and controls (n = 27) to dissect gene regulatory changes caused by ASXL1 mutations. We asked whether DNA methylation epigenetic and transcriptional networks were shared between BOS and AML with ASXL1 mutations. AML is a heterogeneous disorder and often harbors multiple genetic mutations and chromosomal abnormalities that drive cancer evolution. Using The Cancer Genome Atlas (TCGA), we identified DNAm profiles of AML cases with and without ASXL1 mutations. We used the publicly available methylation data to cluster these samples using CpG sites used in our previously validated BOS DNA methylation episignature. When clustering all individuals with AML and individuals with BOS, individuals with AML associated-ASXL1 mutations cluster more closely with individuals with BOS, whereas individuals with AML and no ASXL1 mutations cluster separately. To assess transcriptomic signatures, we compared RNA-seq data from 27 AML cases with ASXL1 mutations from the Beat AML cohort with non-AML blood controls with the differential gene expression analysis of our BOS cases compared with controls. After correcting for batch effects, we identified 821 genes with an absolute fold change greater than 1.5 that were shared between both data sets. A majority of the changes occur in the same direction (615/821, 74.9%) with 53.1% (327/615) of DEGs showing increased gene expression associated with presence of ASXL1 mutations. Overall, we have demonstrated clear links in the gene regulatory pathway dysregulation driven by ASXL1 across distinct disease entities: Bohring Opitz Syndrome (BOS) and AML.