Acute myeloid leukemia ontogeny is defined by distinct somatic mutations

Blood. 2015 Feb 26;125(9):1367-76. doi: 10.1182/blood-2014-11-610543. Epub 2014 Dec 30.

Abstract

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.

Publication types

  • Research Support, N.I.H., Extramural
  • Research Support, Non-U.S. Gov't

MeSH terms

  • 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
  • Polycomb Repressive Complex 2 / genetics
  • Prognosis
  • Prospective Studies
  • Proto-Oncogene Proteins / genetics
  • RNA Splicing Factors
  • Remission Induction
  • Repressor Proteins / genetics
  • Ribonucleoprotein, U2 Small Nuclear / genetics
  • Ribonucleoproteins / genetics
  • Serine-Arginine Splicing Factors
  • Splicing Factor U2AF
  • Survival Rate

Substances

  • ASXL1 protein, human
  • Antigens, Nuclear
  • BCOR protein, human
  • Biomarkers, Tumor
  • Cell Cycle Proteins
  • Nuclear Proteins
  • Phosphoproteins
  • Proto-Oncogene Proteins
  • RNA Splicing Factors
  • Repressor Proteins
  • Ribonucleoprotein, U2 Small Nuclear
  • Ribonucleoproteins
  • SF3B1 protein, human
  • STAG2 protein, human
  • Splicing Factor U2AF
  • U2AF1 protein, human
  • ZRSR2 protein, human
  • SRSF2 protein, human
  • Serine-Arginine Splicing Factors
  • EZH2 protein, human
  • Enhancer of Zeste Homolog 2 Protein
  • Polycomb Repressive Complex 2

Associated data

  • ClinicalTrials.gov/NCT00715637