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Acute myeloid leukemia ontogeny is defined by distinct somatic mutations

R. Coleman Lindsley, Brenton G. Mar, Emanuele Mazzola, Peter V. Grauman, Sarah Shareef, Steven L. Allen, Arnaud Pigneux, Meir Wetzler, Robert K. Stuart, Harry P. Erba, Lloyd E. Damon, Bayard L. Powell, Neal Lindeman, David P. Steensma, Martha Wadleigh, Daniel J. DeAngelo, Donna Neuberg, Richard M. Stone and Benjamin L. Ebert

Key points

  • 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.

Abstract

Acute myeloid leukemia (AML) can develop following an antecedent myeloid malignancy (secondary AML; s-AML), following 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 CR rate, more frequent re-induction, and decreased event-free survival.

  • Submitted November 5, 2014.
  • Accepted December 12, 2014.