Acute myeloid leukemia ontogeny is defined by distinct somatic mutations

• Published in: Blood Vol. 125; no. 9; pp. 1367 - 1376
• Main Authors: Lindsley, R. Coleman, Mar, Brenton G., Mazzola, Emanuele, Grauman, Peter V., Shareef, Sarah, Allen, Steven L., Pigneux, Arnaud, Wetzler, Meir, Stuart, Robert K., Erba, Harry P., Damon, Lloyd E., Powell, Bayard L., Lindeman, Neal, Steensma, David P., Wadleigh, Martha, DeAngelo, Daniel J., Neuberg, Donna, Stone, Richard M., Ebert, Benjamin L.
• Format: Journal Article
• Language: English
• Published: United States Elsevier Inc 26.02.2015; American Society of Hematology
• Series: Myeloid Neoplasia
• Subjects: Antigens, Nuclear - genetics; Biomarkers, Tumor - genetics; Cell Cycle Proteins; DNA Mutational Analysis; Enhancer of Zeste Homolog 2 Protein; Follow-Up Studies; Humans; Leukemia, Myeloid, Acute - diagnosis; Leukemia, Myeloid, Acute - genetics; Leukemia, Myeloid, Acute - mortality; Mutation - genetics; Neoplasm Staging; Neoplasms, Second Primary - diagnosis; Neoplasms, Second Primary - genetics; Neoplasms, Second Primary - mortality; Nuclear Proteins - genetics; Phosphoproteins - genetics; Plenary Paper; Polycomb Repressive Complex 2 - genetics; Prognosis; Prospective Studies; Proto-Oncogene Proteins - genetics; Remission Induction; Repressor Proteins - genetics; Ribonucleoprotein, U2 Small Nuclear - genetics; Ribonucleoproteins - genetics; RNA Splicing Factors; Serine-Arginine Splicing Factors; Splicing Factor U2AF; Survival Rate
• ISSN: 0006-4971; 1528-0020
• DOI: 10.1182/blood-2014-11-610543

Acute myeloid leukemia (AML) can develop after an antecedent myeloid malignancy (secondary AML [s-AML]), after leukemogenic therapy (therapy-related AML [t-AML]), or without an identifiable prodrome or known exposure (de novo AML). The genetic basis of these distinct pathways of AML development has not been determined. We performed targeted mutational analysis of 194 patients with rigorously defined s-AML or t-AML and 105 unselected AML patients. The presence of a mutation in SRSF2, SF3B1, U2AF1, ZRSR2, ASXL1, EZH2, BCOR, or STAG2 was >95% specific for the diagnosis of s-AML. Analysis of serial samples from individual patients revealed that these mutations occur early in leukemogenesis and often persist in clonal remissions. In t-AML and elderly de novo AML populations, these alterations define a distinct genetic subtype that shares clinicopathologic properties with clinically confirmed s-AML and highlights a subset of patients with worse clinical outcomes, including a lower complete remission rate, more frequent reinduction, and decreased event-free survival. This trial was registered at www.clinicaltrials.gov as #NCT00715637. •The presence of a mutation in SRSF2, SF3B1, U2AF1, ZRSR2, ASXL1, EZH2, BCOR, or STAG2 is highly specific for secondary AML.•Secondary-type mutations define an s-AML–like disease within t-AML and elderly de novo AML that underlies clinical heterogeneity.