Role of ASXL1 in hematopoiesis and myeloid diseases

Published:September 29, 2022DOI:


      • ASXL1 hotspot mutations around codon G646 are prevalent in myeloid diseases but are rarely identified in clonal hematopoiesis of indeterminate potential, suggesting that they are highly pathogenic and confer a higher risk of the development of myeloid diseases.
      • Although genetic studies conducted in mice suggest that they are loss-of-function and gain-of-new-function at the physiologic level, overexpression studies in transgenic mice and cell lines indicate that they are dominant-negative and gain-of-function. Additional rigorous investigations are needed to provide a definitive answer to this question.
      • ASXL1 mutations are associated with poor prognosis in all myeloid diseases, perhaps owing to the reduced response to the current treatment options.
      • We recently discovered that Asxl1 loss cooperates with oncogenic Nras in mice to reprogram the immune microenvironment and drive leukemic transformation. Our study provides a strong rationale to develop combined targeted therapy and immunotherapy for treating patients with leukemia with concurrent ASXL1 and NRAS mutations.
      Next-generation sequencing technology, including whole-exome or whole-genome sequencing and target gene sequencing, has allowed the molecular characterization of somatic mutation spectrums in hematologic diseases. Mutations in Additional sex combs-like 1 (ASXL1), a chromatin regulator, are identified in clonal hematopoiesis of indeterminate potential (CHIP), indicating ASXL1 mutations as early events in leukemogenesis. Not surprisingly, they occur at high frequency in myeloid malignancies and are associated with poor prognosis. Therefore, understanding how mutant ASXL1 drives clonal expansion and leukemogenesis will serve as the basis for the future development of preventative and/or therapeutic strategies for myeloid diseases with ASXL1 mutations. Here, we discuss the biology of ASXL1 and its role in controlling normal and malignant hematopoiesis. In addition, we review the clinical relevance of ASXL1 mutations in CHIP and myeloid diseases.
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