title: Acute myeloid leukemia ontogeny is defined by distinct somatic mutations.
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.
authors.affiliation: Department of Medical Oncology, Division of Hematological Malignancies.
authors.forename: R Coleman
authors.initials: RC
authors.lastname: Lindsley
authors.affiliation: Department of Pediatric Oncology, and.
authors.forename: Brenton G
authors.initials: BG
authors.lastname: Mar
authors.affiliation: Department of Biostatistics and Computational Biology, Dana Farber Cancer Institute, Boston MA;
authors.forename: Emanuele
authors.initials: E
authors.lastname: Mazzola
authors.affiliation: Division of Hematology, Brigham and Women's Hospital, Harvard Medical School, Boston, MA;
authors.forename: Peter V
authors.initials: PV
authors.lastname: Grauman
authors.affiliation: Division of Hematology, Brigham and Women's Hospital, Harvard Medical School, Boston, MA;
authors.forename: Sarah
authors.initials: S
authors.lastname: Shareef
authors.affiliation: Hofstra North Shore-LIJ School of Medicine, Hempstead, NY;
authors.forename: Steven L
authors.initials: SL
authors.lastname: Allen
authors.affiliation: Hôpital Haut-Leveque, Centre Hospitalier Universitaire Bordeaux, Pessac, France;
authors.forename: Arnaud
authors.initials: A
authors.lastname: Pigneux
authors.affiliation: Roswell Park Cancer Institute, Buffalo, NY;
authors.forename: Meir
authors.initials: M
authors.lastname: Wetzler
authors.affiliation: Hollings Cancer Center, Medical University of South Carolina, Charleston, SC;
authors.forename: Robert K
authors.initials: RK
authors.lastname: Stuart
authors.affiliation: Division of Hematology and Oncology, University of Alabama, Birmingham, Birmingham, AL;
authors.forename: Harry P
authors.initials: HP
authors.lastname: Erba
authors.affiliation: Helen Diller Family Comprehensive Cancer Center, The University of California, San Francisco, CA;
authors.forename: Lloyd E
authors.initials: LE
authors.lastname: Damon
authors.affiliation: Comprehensive Cancer Center of Wake Forest University, Winston Salem, NC; and.
authors.forename: Bayard L
authors.initials: BL
authors.lastname: Powell
authors.affiliation: Department of Pathology, Brigham and Women's Hospital, Harvard Medical School, Boston, MA.
authors.forename: Neal
authors.initials: N
authors.lastname: Lindeman
authors.affiliation: Department of Medical Oncology, Division of Hematological Malignancies.
authors.forename: David P
authors.initials: DP
authors.lastname: Steensma
authors.affiliation: Department of Medical Oncology, Division of Hematological Malignancies.
authors.forename: Martha
authors.initials: M
authors.lastname: Wadleigh
authors.affiliation: Department of Medical Oncology, Division of Hematological Malignancies.
authors.forename: Daniel J
authors.initials: DJ
authors.lastname: DeAngelo
authors.affiliation: Department of Biostatistics and Computational Biology, Dana Farber Cancer Institute, Boston MA;
authors.forename: Donna
authors.initials: D
authors.lastname: Neuberg
authors.affiliation: Department of Medical Oncology, Division of Hematological Malignancies.
authors.forename: Richard M
authors.initials: RM
authors.lastname: Stone
authors.affiliation: Division of Hematology, Brigham and Women's Hospital, Harvard Medical School, Boston, MA;
authors.forename: Benjamin L
authors.initials: BL
authors.lastname: Ebert
mesh_terms: D034961:Antigens, Nuclear / Q000235:genetics; D014408:Biomarkers, Tumor / Q000235:genetics*; D018797:Cell Cycle Proteins; D004252:DNA Mutational Analysis; D000071221:Enhancer of Zeste Homolog 2 Protein; D005500:Follow-Up Studies; D006801:Humans; D015470:Leukemia, Myeloid, Acute / Q000175:diagnosis / Q000235:genetics* / Q000401:mortality; D009154:Mutation / Q000235:genetics*; D009367:Neoplasm Staging; D016609:Neoplasms, Second Primary / Q000175:diagnosis / Q000235:genetics* / Q000401:mortality; D009687:Nuclear Proteins / Q000235:genetics; D010750:Phosphoproteins / Q000235:genetics; D063151:Polycomb Repressive Complex 2 / Q000235:genetics; D011379:Prognosis; D011446:Prospective Studies; D011518:Proto-Oncogene Proteins / Q000235:genetics; D000072260:RNA Splicing Factors; D012074:Remission Induction; D012097:Repressor Proteins / Q000235:genetics; D017413:Ribonucleoprotein, U2 Small Nuclear / Q000235:genetics; D012261:Ribonucleoproteins / Q000235:genetics; D000068103:Serine-Arginine Splicing Factors; D000072668:Splicing Factor U2AF; D015996:Survival Rate; D000097722:Cohesins
chemical_list: D034961:Antigens, Nuclear; D014408:Biomarkers, Tumor; D018797:Cell Cycle Proteins; D000071221:Enhancer of Zeste Homolog 2 Protein; D009687:Nuclear Proteins; D010750:Phosphoproteins; D063151:Polycomb Repressive Complex 2; D011518:Proto-Oncogene Proteins; D000072260:RNA Splicing Factors; D012097:Repressor Proteins; D017413:Ribonucleoprotein, U2 Small Nuclear; D012261:Ribonucleoproteins; D000068103:Serine-Arginine Splicing Factors; D000072668:Splicing Factor U2AF; C473949:ASXL1 protein, human; C411984:BCOR protein, human; C112491:SF3B1 protein, human; C508565:STAG2 protein, human; D000097722:Cohesins; C076753:U2AF1 protein, human; C484334:ZRSR2 protein, human; C073288:SRSF2 protein, human; C498409:EZH2 protein, human