CEBPA mutations in 4708 patients with acute myeloid leukemia: differential impact of bZIP and TAD mutations on outcome

Abstract

Biallelic mutations of the CEBPA gene (CEBPAbi) define a distinct entity associated with favorable prognosis, however the role of monoallelic mutations (CEBPAsm) is poorly understood. We retrospectively analyzed 4708 adult AML patients recruited into Study Alliance Leukemia trials to investigate the prognostic impact of CEBPAsm. CEBPA mutations were identified in 240 patients (5.1%), 131 CEBPAbi and 109 CEBPAsm (60 affecting the amino-terminal transactivation domains (CEBPAsmTAD) and 49 the carboxy-terminal DNA-binding or basic leucine zipper region (CEBPAsmbZIP)). Interestingly, CEBPAbi and CEBPAsmbZIP patients shared several clinical factors, i.e. were significantly younger (median 46 years and 50 years) and had higher WBC counts at diagnosis (median 23.7 and 35.7 109/l) compared to CEBPAsmTAD patients (median age 63 yrs., median WBC 13.1 109/l; p<.001). Co-mutations were also similar in both groups, e.g. GATA2 mutations (35.1% CEBPAbi; 36.7% CEBPAsmbZIP vs. 6.7% CEBPAsmTAD; p<.001) or NPM1 mutations (3.1% CEBPAbi; 8.2% CEBPAsmbZIP vs. 38.3% CEBPAsmTAD; p<.001). CEBPAbi and CEBPAsmbZIP, but not CEBPAsmTAD were associated with significantly improved overall (median OS: 103 and 63 vs. 13 months) and event-free survival (median EFS: 20.7 and 17.1 vs. 5.7 months), in univariate and multivariable analyses. More detailed analysis revealed that the clinical and molecular features as well as the favorable survival were confined to patients showing in-frame mutations in bZIP (CEBPAbZIP-inf). When grouping patients into CEBPAbZIP-inf and CEBPAother (including CEBPAsmTAD and other non-CEBPAbZIP-inf patients), only CEBPAbZIP-inf patients showed superior CR rates and the longest median OS and EFS, arguing for a previously undefined prognostic role of this type of mutations.

C/EBPα confers dependence to fatty acid anabolic pathways and vulnerability to lipid oxidative stress in FLT3-mutant leukemia

“…C/AAT-enhancer binding protein α (C/EBPα, encoded by the CEBPA gene) is a key transcription factor of myeloid differentiation 21 . Different CEBPA mutations are detected in 5-9% of AML cases at diagnosis, with prognostic implications 1,22 . Moreover, CEBPA expression is downregulated in AML subtypes such as those harboring RUNX1 – CBF2T1 fusion gene, which participate to differentiation block, highlighting the importance of C/EBPα in leukemogenesis 23 .…”

Molecular profiling and clinical implications of patients with acute myeloid leukemia and extramedullary manifestations

“…However, its role in the formation of EM is insufficiently defined and further investigations are warranted to shed light on the mechanisms of how disrupted SHP2 signaling drives EM formation. While mutations of CEBPA were associated with significantly decreased odds of EM AML in our cohort, this effect was not seen individually in biallelic mutations of CEBPA , CEBPA-TAD or CEBPA-bZIP , rendering the mechanism unclear and thereby calling for more detailed investigations as subtypes of CEBPA have been reported to show differences in clinical outcomes [ 18 ].…”

“…Cytogenetic profiling was done using standard techniques for chromosome banding and fluorescence in situ hybridization (FISH). Molecular profiling was done using high resolution fragment analysis for FLT3 -ITD [ 16 ], NPM1 [ 17 ] or CEBPA [ 18 ]. For additional alterations, characterization was done using the TruSight Myeloid assay (Illumina, San Diego, CA, USA) as described in detail previously [ 19 , 20 ].…”

The underlying molecular mechanisms and biomarkers of plaque vulnerability based on bioinformatics analysis

“…CEBPA as a myeloid transcription factor, its mutations play an important role in the pathogenesis of hematological tumors [19,20] . But it is less well studied in cardiovascular disease and in promoting atherosclerosis.…”