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

• Published in: Blood Vol. 125; no. 3; pp. 516 - 524
• Main Authors: Stieglitz, Elliot, Troup, Camille B., Gelston, Laura C., Haliburton, John, Chow, Eric D., Yu, Kristie B., Akutagawa, Jon, Taylor-Weiner, Amaro N., Liu, Y. Lucy, Wang, Yong-Dong, Beckman, Kyle, Emanuel, Peter D., Braun, Benjamin S., Abate, Adam, Gerbing, Robert B., Alonzo, Todd A., Loh, Mignon L.
• Format: Journal Article
• Language: English
• Published: United States Elsevier Inc 15.01.2015; American Society of Hematology
• Subjects: 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; Myeloid Neoplasia; Neoplasm Staging; Nuclear Proteins - genetics; Prognosis; Survival Rate
• ISSN: 0006-4971; 1528-0020
• DOI: 10.1182/blood-2014-09-601690

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). •Mutations in SETBP1 can be detected using droplet digital polymerase chain reaction in at least 30% of patients with JMML and are associated with a dismal prognosis.•Patients harboring rare cells with mutant SETBP1 at diagnosis should be considered candidates for swift hematopoietic stem cell transplant.