CTNNA1 hypermethylation, a frequent event in acute myeloid leukemia, is independently associated with an adverse outcome

Abstract

The aim of this study is to evaluate the frequency of CTNNA1 hypermethylation in acute myeloid leukemia (AML) patients in an attempt to improve molecular prognostic model. CTNNA1 promoter methylation levels in 319 newly diagnosed AML patients were detected using quantitative methylation-specific polymerase chain reaction (qMS-PCR). Furthermore, hematological characteristics, cytogenetic abnormalities, and genetic mutation status were analyzed, followed by assessment of clinical impact. Our findings demonstrated that CTNNA1 hypermethylation was observed in 25% AML patients. Hypermethylation of the CTNNA1 promoter was associated with unfavorable karyotype, and also possessed the higher frequency of coexisting with ASXL1 and RUNX1 mutations. Patients with CTNNA1 hypermethylation exhibited the shorter relapse-free survival (RFS) and overall survival (OS) in the whole AML and non-M3 AML patients. Moreover, patients with the higher methylation levels had more aggressive course than those with relative lower levels. In multivariate analyses, CTNNA1 hypermethylation was an independent factor predicting for poor RFS, but not for OS. In conclusion, CTNNA1 hypermethylation may be a reliable factor for improving prognostic molecular model for AML.

Keywords: CTNNA1; acute myeloid leukemia; clinical impact; hypermethylation; survival.

Figure 1. CTNNA1 mRNA levels and methylation levels in AML patients

A. Relative expression of the CTNNA1 gene in 319 AML patients and 30 healthy controls. AML patients exhibited the lower CTNNA1 mRNA levels than healthy controls. B. Relative expression of the CTNNA1 gene was detected in the patients with CTNNA1 hypermethylation and the cases with non-methylation. Patients with CTNNA1 hypermethylation exhibited lower mRNA transcript levels than those with non-methylation C. There was a negative correlation between CTNNA1 methylation levels and CTNNA1 transcripts levels (R=−0.364, P=0.011).

Figure 2. Hypermethylation of the CTNNA1 promoter in five AML patients by bisulfate sequencing at different clinical stages

Methylation rates decreased during hematological complete remission.

Figure 3. The spectrum of gene mutations in 319 AML patients with hypermethylation and non-methylation of the CTNNA1 gene

Figure 4. Kaplan-Meier curves for poor relapse-free survival (RFS) and overall survival (OS) in AML patients revealed that CTNNA1 hypermethylation indicated the shorter survival

A. and B., In all 319 AML patients, the cases with CTNNA1 hypermethylation (n=79) had poor RFS and OS compared to those with non-methylation (n=240) (P=0.001 and P=0.002, respectively). C. and D., In non-M3 AML patients, the cases with CTNNA1 hypermethylation (n=75) had inferior RFS and OS compared to those with non-methylation (n=220) (P=0.001 and P=0.003, respectively). E. and F. Patients with higher CTNNA1 methylation levels (n=19) had adverse RFS and OS compared to individuals with lower methylation levels (n=60) (P = 0.014 and P=0.003, respectively).