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Acute Leukemias

The role of different genetic subtypes of CEBPA mutated AML

Abstract

The prognostic impact of mutations in the CCAAT/enhancer binding protein α (CEBPA) gene was evaluated in the context of concomitant molecular mutations and cytogenetic aberrations in acute myeloid leukemia (AML). CEBPA was screened in a cohort of 2296 adult AML cases. Of 244 patients (10.6%) with CEBPA mutations, 140 cases (6.1%) were single-mutated (CEBPAsm) and 104 cases (4.5%) were double-mutated (CEBPAdm). Cytogenetic analysis revealed normal karyotype in 172/244 (70.5%) of CEBPAmut cases, whereas in 72/244 cases (29.5%) at least one cytogenetic aberration was detected. Concurrent molecular mutations were seen less frequently in CEBPAdm than in CEBPAsm AML cases (69.2% vs 88.6% P<0.001). In detail, the spectrum of concurrent mutations was different in both groups with the frequent occurrence of GATA1 and WT1 mutations in CEBPAdm patients. In contrast, FLT3-ITD, NPM1, ASXL1 and RUNX1 mutations were detected more frequently in CEBPAsm cases. Favorable outcome was restricted to CEBPAdm cases and remained an independent prognostic factor for a favorable outcome in multivariate analysis (hazard ratio: 0.438, P=0.020). Outcome in CEBPAsm cases strongly depended on concurrent FLT3-ITD. In conclusion, we propose that only CEBPAdm should be considered as an entity in the WHO classification of AML and should be clearly distinguished from CEBPAsm AML.

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Acknowledgements

We thank all clinicians for sending samples to our laboratory for diagnostic purposes, and for providing clinical information and follow-up data. We thank Roche Diagnostics GmbH, for providing CEBPA oligonucleotide primer plates as part of the IRON-II research study framework. In addition, we would like to thank all co-workers at the MLL (Munich Leukemia Laboratory) for bringing together many aspects in the field of leukemia diagnostics and research. In addition, we thank Elke Roos and Dominic Rose for preparing and revising figures and submitting the manuscript.

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Correspondence to S Schnittger.

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CH, WK, TH and SuS have equity ownership of MLL Munich Leukemia Laboratory GmbH. AF, TA, CE, SW, FD, AK, SJ and SoS are employed by MLL Munich Leukemia Laboratory GmbH.

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AF investigated the mutation status of CEBPA, analyzed the data and wrote the manuscript; CH was responsible for chromosome analysis; TA collected and documented clinical data and compiled statistical analyses; VG, CE, SW, FD, AK, SJ and SoS performed molecular analyses; WK was responsible for immunophenotyping and was involved in statistical analyses; TH was responsible for cytomorphologic analysis and was involved in the collection of clinical data. SS was the principle investigator of the study and wrote the manuscript. All authors read and contributed to the final version of the manuscript.

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Fasan, A., Haferlach, C., Alpermann, T. et al. The role of different genetic subtypes of CEBPA mutated AML. Leukemia 28, 794–803 (2014). https://doi.org/10.1038/leu.2013.273

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