Mixed-phenotype acute leukemia (MPAL) exhibits frequent mutations in DNMT3A and activated signaling genes

Exp Hematol. 2016 Aug;44(8):740-4. doi: 10.1016/j.exphem.2016.05.003. Epub 2016 May 18.


Mixed-phenotype acute leukemia (MPAL) is a heterogeneous group of poor-prognosis leukemias with immunophenotypic features of at least two cell lineages. The full spectrum of genetic mutations in this rare disease has not been elucidated, limiting our understanding of disease pathogenesis and our ability to devise targeted therapeutic strategies. Here, we sought to define the mutational landscape of MPAL by performing whole-exome sequencing on samples from 23 adult and pediatric MPAL patients. We identified frequent mutations of epigenetic modifiers, most notably mutations of DNMT3A, in 33% of adult MPAL patients. Mutations of activated signaling pathways, tumor suppressors, and transcription factors were also frequent. Importantly, many of the identified mutations are potentially therapeutically targetable, with agents currently available or in various stages of clinical development. Therefore, the mutational spectrum that we have identified provides potential biological insights and is likely to have clinical relevance for patients with this poor-prognosis disease.

MeSH terms

  • Adolescent
  • Adult
  • Clonal Evolution / genetics
  • Cluster Analysis
  • DNA (Cytosine-5-)-Methyltransferases / genetics*
  • DNA Methyltransferase 3A
  • Epigenesis, Genetic
  • Exome
  • Gene Expression Profiling
  • Gene Expression Regulation, Leukemic
  • High-Throughput Nucleotide Sequencing
  • Humans
  • Leukemia, Biphenotypic, Acute / genetics*
  • Leukemia, Biphenotypic, Acute / metabolism*
  • Middle Aged
  • Mutation*
  • Signal Transduction*
  • Young Adult


  • DNMT3A protein, human
  • DNA (Cytosine-5-)-Methyltransferases
  • DNA Methyltransferase 3A