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

Authors

Moritz Binder, Mayo Clinic
Ryan M. Carr, Mayo Clinic
Terra L. Lasho, Mayo Clinic
Christy M. Finke, Mayo Clinic
Abhishek A. Mangaonkar, Mayo Clinic
Christopher L. Pin, Western UniversityFollow
Kurt R. Berger, Western University
Amelia Mazzone, Mayo Clinic
Sandeep Potluri, University of Birmingham
Tamas Ordog, Mayo Clinic
Keith D. Robertson, Mayo Clinic
David L. Marks, Mayo Clinic
Martin E. Fernandez-Zapico, Mayo Clinic
Alexandre Gaspar-Maia, Mayo Clinic
Mrinal M. Patnaik, Mayo Clinic

Document Type

Article

Publication Date

12-1-2022

Journal

Nature Communications

Volume

13

Issue

1

URL with Digital Object Identifier

10.1038/s41467-022-29142-6

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 ASXL1MT in chronic myelomonocytic leukemia (CMML). ASXL1MT are associated with a loss of repressive histone methylation and increase in permissive histone methylation and acetylation in promoter regions. ASXL1MT are 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 ASXL1MT CMML, forming an important framework for the development of novel therapeutic strategies targeting oncogenic cis interactions.