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

Acute myeloid leukemia ontogeny is defined by distinct somatic mutations

R Coleman Lindsley  1 , Brenton G Mar  2 , Emanuele Mazzola  3 , Peter V Grauman  4 , Sarah Shareef  4 , Steven L Allen  5 , Arnaud Pigneux  6 , Meir Wetzler  7 , Robert K Stuart  8 , Harry P Erba  9 , Lloyd E Damon  10 , Bayard L Powell  11 , Neal Lindeman  12 , David P Steensma  1 , Martha Wadleigh  1 , Daniel J DeAngelo  1 , Donna Neuberg  3 , Richard M Stone  1 , Benjamin L Ebert  4
Affiliations

Acute myeloid leukemia ontogeny is defined by distinct somatic mutations

R Coleman Lindsley et al. Blood. .

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.

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Figures

Figure 1
Figure 1
Spectrum and ontogeny specificity of myeloid driver mutations in s-AML. (A) A comutation plot shows nonsynonymous mutations in individual genes, grouped into categories, as labeled on the left. Mutations are depicted by colored bars and each column represents 1 of the 93 sequenced subjects. Colors reflect ontogeny specificity of mutated genes, as described in (B). (B) Shown is the association between individual mutated genes and clinically defined s-AML or de novo AML ontogeny, as depicted by odds ratio on a log10 scale. Colors indicate genes with >95% specificity for s-AML (blue), >95% specificity for de novo AML (red), or <95% specificity for s-AML or de novo AML (yellow or green). The number and frequency cases with mutations in each gene in s-AML and de novo AML cases are shown on the right.
Figure 2
Figure 2
Mutations in therapy-related AML. A comutation plot shows nonsynonymous mutations in individual genes, as labeled on the left. Mutations are depicted by colored bars, and each column represents 1 of the 101 sequenced subjects. Colors reflect ontogeny specificity of mutated genes, as described in Figure 1. Genetic ontogeny groups are labeled on the top.
Figure 3
Figure 3
Ontogeny-based genetic classification defines clinically distinct t-AML subgroups. (A-B) Induction outcomes in clinically defined t-AML patients according to genetic ontogeny group. (A) Morphologic CR outcomes according to genetic ontogeny group among clinically defined t-AML patients receiving standard induction chemotherapy. (B) Shown is the number of induction cycles among t-AML patients achieving CR. (C) Within clinically defined t-AML, genetic classification identifies subgroups with distinct characteristics, including number of recurrent driver mutations per case, number of cytogenetic abnormalities per case, and age. In box plots, center lines show the median value, box limits indicate the 25th and 75th percentiles, whiskers extend to the 10th and 90th percentiles, and outliers are represented by dots. (D) Distribution of genetic ontogeny groups in t-AML patients according to age group. (E) History of prior chemotherapy or radiation exposure based on genetic ontogeny class.
Figure 4
Figure 4
Analysis of serial samples. Scatter plots showing variant allele fractions (VAF) at time of paired samples at (A) MDS and s-AML and (B) diagnosis and morphologic CR. Colors show ontogeny specificity of mutated genes including secondary-type (blue); TP53 (green); and de novo/pan-AML subsets, including RAS pathway and myeloid transcription factors (red), TET2 and DNMT3A (yellow), and other pan-AML (gray). Mutations were categorized as new if they were detected in s-AML but present below 1% allele frequency in MDS (85%), or if their allele frequency increased from ≤10% in MDS to >30% in the subsequent s-AML (15%). Mutations were labeled as selectively lost only if variant allele fraction was <0.5% at remission. (C) Pie chart showing s-AML progression mutations by functional class. (D) Representative fish plots from 2 cases with subclonal remissions showing clonal architecture at diagnosis (indicated by a red line—AML) and after treatment at time of morphologic CR (indicated by a red line—CR). In both cases, clonal remission is characterized by disappearance of progression mutations and relative persistence of founder mutations despite the absence of bone marrow myeloblasts.
Figure 5
Figure 5
Mutations in an unselected cohort of AML patients. A comutation plot shows nonsynonymous mutations in individual genes, grouped into categories, as labeled on the left. Mutations are depicted by colored bars, and each column represents 1 of the 105 sequenced subjects. Colors reflect ontogeny specificity of mutated genes, as described in Figure 1.
Figure 6
Figure 6
Ontogeny-based genetic classification defines clinically distinct de novo AML subgroups. (A) Within clinically defined de novo AML, genetic classification identifies subgroups with distinct characteristics, including number of recurrent driver mutations per case, number of cytogenetic abnormalities per case, and age. Box plots are described in Figure 3. (B) Proportion of patients achieving CR after intensive induction chemotherapy based on genetic subtype among older de novo AML patients (left) and clinically defined s-AML patients (right). (C) Event-free survival in clinically defined de novo AML patients age ≥60 years according to genetic ontogeny group. Curves show patients with de novo/pan-AML (red), secondary-type (blue), and TP53 (green) mutations.
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