Somatic mutations in ASXL1 have been identified in patients with myeloid malignancies and are associated with worsened overall survival in AML and MDS patients. However the mechanisms of myeloid transformation of ASXL1 mutations had not been delineated. Medical oncologist Omar Abdel-Wahab discusses studies that assessed the functional implications of ASXL1 mutations in the hematopoietic compartment.
Results reveal that ASXL1 mutations result in a loss of function and suggest a specific role for ASXL1 in epigenetic regulation of gene expression by facilitating PRC2-mediated transcriptional repression of known leukemic oncogenes. This data validates the importance of ASXL1 mutations in the pathogenesis of myeloid malignancies and provides insight into how mutations that inhibit PRC2 function contribute to myeloid transformation through epigenetic dysregulation of specific target genes.