Oncogenic gene expression and epigenetic remodeling of cis-regulatory elements in ASXL1-mutant chronic myelomonocytic leukemia

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Abstract
Myeloid neoplasms are clonal hematopoietic stem cell disorders driven by the sequential acquisition of recurrent genetic lesions. Truncating mutations in the chromatin remodeler ASXL1 (ASXL1MT) are associated with a high-risk disease phenotype with increased proliferation, epigenetic therapeutic resistance, and poor survival outcomes. We performed a multi-omics interrogation to define gene expression and chromatin remodeling associated with ASXL1MTin chronic myelomonocytic leukemia (CMML). ASXL1MTare associated with a loss of repressive histone methylation and increase in permissive histone methylation and acetylation in promoter regions. ASXL1MTare further associated with de novo accessibility of distal enhancers binding ETS transcription factors, targeting important leukemogenic driver genes. Chromatin remodeling of promoters and enhancers is strongly associated with gene expression and heterogenous among overexpressed genes. These results provide a comprehensive map of the transcriptome and chromatin landscape of ASXL1MTCMML, forming an important framework for the development of novel therapeutic strategies targeting oncogenic cis interactions.
Funding Information
  • U.S. Department of Health & Human Services | NIH | National Center for Advancing Translational Sciences (TR000136)
  • Mayo Clinic Center For Individualized Medicine Henry J. Predolin Foundation Gerstner Family Foundation

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