Subclonal mutations in SETBP1 confer a poor prognosis in juvenile myelomonocytic leukemia

Blood. 2015 Jan 15;125(3):516-24. doi: 10.1182/blood-2014-09-601690. Epub 2014 Nov 13.


Juvenile myelomonocytic leukemia (JMML) is an aggressive myeloproliferative neoplasm of childhood associated with a poor prognosis. Recently, massively parallel sequencing has identified recurrent mutations in the SKI domain of SETBP1 in a variety of myeloid disorders. These lesions were detected in nearly 10% of patients with JMML and have been characterized as secondary events. We hypothesized that rare subclones with SETBP1 mutations are present at diagnosis in a large portion of patients who relapse, but are below the limits of detection for conventional deep sequencing platforms. Using droplet digital polymerase chain reaction, we identified SETBP1 mutations in 17/56 (30%) of patients who were treated in the Children's Oncology Group sponsored clinical trial, AAML0122. Five-year event-free survival in patients with SETBP1 mutations was 18% ± 9% compared with 51% ± 8% for those without mutations (P = .006).

Publication types

  • Research Support, N.I.H., Extramural

MeSH terms

  • Carrier Proteins / genetics*
  • Child, Preschool
  • Female
  • Follow-Up Studies
  • High-Throughput Nucleotide Sequencing
  • Humans
  • Infant
  • Infant, Newborn
  • Leukemia, Myelomonocytic, Juvenile / genetics*
  • Leukemia, Myelomonocytic, Juvenile / pathology
  • Male
  • Mutation / genetics*
  • Neoplasm Staging
  • Nuclear Proteins / genetics*
  • Prognosis
  • Survival Rate


  • Carrier Proteins
  • Nuclear Proteins
  • SETBP1 protein, human