Comprehensive genomic profiling reveals molecular subsets of ASXL1-mutated myeloid neoplasms

Leuk Lymphoma. 2024 Feb;65(2):209-218. doi: 10.1080/10428194.2023.2277672. Epub 2024 Jan 24.

Abstract

A large-scale genomic analysis of patients with ASXL1-mutated myeloid disease has not been performed to date. We reviewed comprehensive genomic profiling results from 6043 adults to characterize clinicopathologic features and co-mutation patterns by ASXL1 mutation status. ASXL1 mutations occurred in 1414 patients (23%). Mutation co-occurrence testing revealed strong co-occurrence (p < 0.01) between mutations in ASXL1 and nine genes (SRSF2, U2AF1, RUNX1, SETBP1, EZH2, STAG2, CUX1, CSF3R, CBL). Further analysis of patients with these co-mutations yielded several novel findings. Co-mutation patterns supported that ASXL1/SF3B1 co-mutation may be biologically distinct from ASXL1/non-SF3B1 spliceosome co-mutation. In AML, ASXL1/SRSF2 co-mutated patients frequently harbored STAG2 mutations (42%), which were dependent on the presence of both ASXL1 and SRSF2 mutation (p < 0.05). STAG2 and SETBP1 mutations were also exclusive in ASXL1/SRSF2 co-mutated patients and associated with divergent chronic myeloid phenotypes. Our findings support that certain multi-mutant genotypes may be biologically relevant in ASXL1-mutated myeloid disease.

Keywords: Myeloid leukemias and dysplasias; molecular genetics; myeloproliferative disorders; neoplasia.

Publication types

  • Review

MeSH terms

  • Adult
  • Genomics
  • Humans
  • Leukemia, Myeloid, Acute* / genetics
  • Mutation
  • Myeloproliferative Disorders* / genetics
  • Neoplasms*
  • Prognosis
  • Repressor Proteins / genetics
  • Spliceosomes / genetics
  • Spliceosomes / pathology
  • Transcription Factors / genetics

Substances

  • Transcription Factors
  • ASXL1 protein, human
  • Repressor Proteins