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. 2009 Mar 26;113(13):3088-91.
doi: 10.1182/blood-2008-09-179895. Epub 2009 Jan 26.

Double CEBPA mutations, but not single CEBPA mutations, define a subgroup of acute myeloid leukemia with a distinctive gene expression profile that is uniquely associated with a favorable outcome

Bas J Wouters  1 , Bob Löwenberg, Claudia A J Erpelinck-Verschueren, Wim L J van Putten, Peter J M Valk, Ruud Delwel
Affiliations

Double CEBPA mutations, but not single CEBPA mutations, define a subgroup of acute myeloid leukemia with a distinctive gene expression profile that is uniquely associated with a favorable outcome

Bas J Wouters et al. Blood. .

Abstract

Mutations in CCAAT/enhancer binding protein alpha (CEBPA) are seen in 5% to 14% of acute myeloid leukemia (AML) and have been associated with a favorable clinical outcome. Most AMLs with CEBPA mutations simultaneously carry 2 mutations (CEBPA(double-mut)), usually biallelic, whereas single heterozygous mutations (CEBPA(single-mut)) are less frequently seen. Using denaturing high-performance liquid chromatography and nucleotide sequencing, we identified among a cohort of 598 newly diagnosed AMLs a subset of 41 CEBPA mutant cases (28 CEBPA(double-mut) and 13 CEBPA(single-mut) cases). CEBPA(double-mut) associated with a unique gene expression profile as well as favorable overall and event-free survival, retained in multivariable analysis that included cytogenetic risk, FLT3-ITD and NPM1 mutation, white blood cell count, and age. In contrast, CEBPA(single-mut) AMLs did not express a discriminating signature and could not be distinguished from wild-type cases as regards clinical outcome. These results demonstrate significant underlying heterogeneity within CEBPA mutation-positive AML with prognostic relevance.

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Figures

Figure 1
Figure 1
Schematic overview of dHPLC analysis, gene expression profiling analysis, and survival estimates. (A) Schematic representation of the CEBPA gene and location of amplicons a, b, and c for polymerase chain reaction, used for dHPLC analysis. Functional regions are depicted: 2 transactivation domains (TAD1 and TAD2) in the N-terminal part, and the bZIP region in the C-terminal part. Nucleotide (nt) position is indicated relative to the main translation start site. Amino acid (aa) numbering and the alternative translation start site at position nt 358 (aa 120) are also depicted. (B) Representative profiles of dHPLC analysis of 1 of the 3 investigated fragments (ie, amplicons b) in a random selection of approximately 90 samples. Heteroduplexes (various colors) are released earlier than homoduplexes (green) and can therefore be recognized as distinct peaks. Time is depicted on the x-axis, and absorbance on the y-axis. (C) A gene expression prediction signature for CEBPAmut AML (irrespective of single- or double-mutant status) was derived in a dataset of 524 AMLs, including 38 CEBPAmut cases. Prediction accuracy for each of the 38 CEBPAmut cases was estimated using repeated 10-fold cross-validation, as detailed in supplemental data. The proportion of correct predictions for the selected 38 CEBPAmut specimens is indicated (top panel). Mutation status is color coded (CEBPAsingle-mut, blue; CEBPAdouble-mut, red). The heatmap in the bottom panel depicts the 19 probe sets in the resulting CEBPAmut gene expression classifier (Table S2, probe set information). Intensity values (log2) were mean centered over the cohort of 524 AML cases; and for visualization purposes, the genes were hierarchically clustered (Euclidian distance, average linkage). Cells represent relative log 2 expression values and have been color coded on a scale ranging from bright green (−3) to bright red (+3), with black indicating no change relative to the mean. (D) Kaplan-Meier estimates of overall survival among CEBPAmut and CEBPAwt AML (log rank test, P = .027). (E) Overall survival among CEBPAdouble-mut versus CEBPAwt AML (P = .004) and versus CEBPAsingle-mut AML (P = .005; pooled P = .012). (F) Event-free survival (EFS) among CEBPAdouble-mut and CEBPAwt AML (P = .005) and versus CEBPAsingle-mut AML (P = .004; pooled P = .008). The cumulative proportion of survival at the intercept (the point where a line crosses the y-axis) reflects the proportion of patients reaching complete remission. Analyses similar to those depicted in panels D-F were performed after splitting the group of CEBPAwt AMLs into those with favorable cytogenetics and those with other cytogenetics. These additional analyses can be found in Figure S4.
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