Characteristics of mutations in acute myeloid leukemia.

BACKGROUND

mutations occur in approximately 20% of AML cases and are associated with changes in DNA methylation. plays an important role in the regulation of hematopoietic progenitor cells and mutation is associated with promoter methylation. We analyzed the characteristics of mutations including their clinical significance in AML and their influence on promoter methylation and expression.

METHODS

A total of 142 adults, recently diagnosed with de novo AML, were enrolled in the study. Mutations in , , and were analyzed by bidirectional Sanger sequencing. We evaluated promoter methylation and expression using pyrosequencing and RT-qPCR.

RESULTS

We identified mutations in 19.7% (N=28) of enrolled patients with AML, which increased to 29.5% when analysis was restricted to cytogenetically normal-AML. Mutations were located on exons from 8-23, and the majority, including R882, were found to be present on exon 23. We also identified a novel frameshift mutation, c.1590delC, in AML with biallelic mutation of . There was no significant difference in promoter methylation according to the presence or type of mutations. expression inversely correlated with promoter methylation and was significantly higher in AML with R882H mutation in . We demonstrated that mutation was associated with poor AML outcomes, especially in cytogenetically normal-AML. The mutation remained as the independent unfavorable prognostic factor after multivariate analysis.

CONCLUSION

We characterized mutations in AML and revealed the association between the mutation and expression and clinical outcome.