Genetic heterogeneity of cytogenetically normal AML with mutations of CEBPA.

Abstract

Biallelic mutations of the CCAAT/enhancer binding protein α (CEBPA) gene define a distinct genetic entity of acute myeloid leukemia (AML) with favorable prognosis. The presence of GATA2 and CSF3R mutations that are specifically associated with this subgroup but not mutated in all samples suggests a genetic heterogeneity of biCEBPA-mutated AML. We characterized the mutational landscape of CEBPA-mutated cytogenetically normal AML by targeted amplicon resequencing. We analyzed 48 biallelically mutated CEBPA (biCEBPA), 32 monoallelically mutated CEBPA (moCEBPA), and 287 wild-type CEBPA (wtCEBPA) patient samples from German AML Cooperative Group studies or registry. Targeted sequencing of 42 genes revealed that moCEBPA patients had significantly more additional mutations and additional mutated genes than biCEBPA patients. Within the group of biCEBPA patients, we identified 2 genetic subgroups defined by the presence or absence of mutations in chromatin/DNA modifiers (C), cohesin complex (C), and splicing (S) genes: biCEBPA CCSpos (25/48 [52%]) and biCEBPA CCSneg (23/48 [48%]). Equivalent subgroups were identified in 51 biCEBPA patients from the Cancer Genome Project. Patients in the biCEBPA CCSpos group were significantly older and had poorer overall survival and lower complete remission rates following intensive chemotherapy regimens compared with patients in the biCEBPA CCSneg group. Patients with available remission samples from the biCEBPA CCSpos group cleared the biCEBPA mutations, but most had persisting CCS mutations in complete remission, suggesting the presence of a preleukemic clone. In conclusion, CCS mutations define a distinct biological subgroup of biCEBPA AML that might refine prognostic classification of AML. This trial was registered at www.clinicaltrials.gov as #NCT00266136 and NCT01382147.

• Authors: Nikola P Konstandin, Friederike Pastore, Tobias Herold, Annika Dufour, Maja Rothenberg-Thurley, Tanja Hinrichsen, Bianka Ksienzyk, Sebastian Tschuri, Stephanie Schneider, Eva Hoster, Wolfgang E Berdel, Bernhard J Woermann, Maria C Sauerland, Jan Braess, Stefan K Bohlander, Hanns-Georg Klein, Wolfgang Hiddemann, Klaus H Metzeler, Karsten Spiekermann
• Journal: Blood advances (Blood Adv) Vol. 2 Issue 20 Pg. 2724-2731 (10 23 2018) ISSN: 2473-9537 [Electronic] United States
• PMID: 30337300 (Publication Type: Journal Article, Research Support, Non-U.S. Gov't)
• Copyright: © 2018 by The American Society of Hematology.

Chemical References

• CCAAT-Enhancer-Binding Protein-alpha
• CCAAT-Enhancer-Binding Proteins
• CEBPA protein, human

Topics

• Adolescent
• Adult
• Aged
• CCAAT-Enhancer-Binding Protein-alpha (genetics)
• CCAAT-Enhancer-Binding Proteins (genetics, metabolism)
• Cytogenetics (methods)
• Female
• Genetic Heterogeneity (drug effects)
• Humans
• Male
• Middle Aged
• Mutation
• Prognosis
• Young Adult