The N-Terminal Amino Acid Mutation Site Is a Potential Biological Marker for Precise Risk Stratification in Pediatric Patients with CEBPA-Dm AML

CCAAT/enhancer-binding protein alpha (CEBPA) mutations are a favorable prognostic factor for acute myeloid leukemia (AML) patients in adult and pediatric. However, several previous studies have examined relapse rate may be as high as 30%.

To explore some features that predict relapse, we found that 33/345 de novo AML patients (9.5%) harbored a mutation in CEBPA, of which 33 patients had 25 (75.8%) harbored CEBPA-dm and 8 (24.2%) harbored CEBPA-sm. Five (15.2%) relapsed patients were all classical CEBPA-dm children. There were no statistically significant differences in clinical characteristics and survival outcomes between CEBPA-sm and CEBPA-dm patients. The classical CEBPA-dm patients with N-terminal mutation sites among amino acid (AA)1-59 were less likely to relapse[n=0(0%) vs. n=5(45.5%), P=0.011] and had superior RFS and EFS than patients with N-terminal mutation sites concentrated in the AA range 60-120 (RFS: 100.0% vs. 41.6±19.7%, P=0.005; EFS: 92.3±7.4% vs. 41.6±19.7%, P=0.03). Gene expression profiling in 9 classical CEBPA-dm patients (including 3 patients in N- terminal AA mutation sites among 1-59 and 6 patients among 60-120) showed that over-expression of PDLIM1 may be an indicator of poor prognosis [RSF of PDLIM1 high vs. low PDLIM1 expression: 33.3±27.2% vs. 100.0%, P=0.053].

When we applied the "adjusted risk stratification", namely N-terminal AA mutation sites used as one of the stratification indicators based on NCCN guidelines, we observed a more pronounced difference in RFS among adjusted risk groups, especially for the 24 cases classical CEBPA-dm patients (P=0.358 vs. P=0.027 for classical CEBPA-dm patients; P=0.028 vs. P=0.022 for classical CEBPA-dm patients who chemotherapy-only). Multivariate analysis identified that higher bone marrow (BM) blast(≥75%) was an independent risk factors for EFS [hazard ratio (HR): 1.51, 95%CI: 1.25-1.84, P=0.032] and normal karyotype was an independent favorable prognostic factor for RFS (HR: 0.31, 95%CI: 0.12-0.59, P=0.049) in classical CEBPA-dm cohort. N-terminal AA sites range 1-59 appeared to be a protective factor for RFS (HR=0.82, 95%CI: 0.61-1.38, P=0.056). In classical CEBPA-dm cohort receiving chemotherapy-only, higher BM blast(≥75%) at diagnosis was independent prognostic factors for RFS and EFS (HR=0.82, 95%CI: 0.61-1.38, P=0.056).

In conclusion, our clinical data suggested that N- terminal AA mutation sites concentrated among 1-59 appear to be a protective factor for RFS in classical CEBPA-dm patients. The "adjusted risk stratification" may be useful in re-assessing the prognosis of classical CEBPA-dm AML particularly in patients belonging to the intermediate-risk subgroup. Over-expression of PDLIM1 may be an indicator of poor prognosis and need to be validated in our future large samples.

No relevant conflicts of interest to declare.