Abstract
BackgroundThe influence of DNMT3A R882 mutations on adult acute myeloid leukemia (AML) prognosis is still controversial presently. The influence of R882 allele ratio on drug response and prognosis of AML is unknown yet. Besides, it is obscure whether anthracyclines are involved in chemoresistance resulted from R882 mutations.MethodsDNMT3A R882 mutations in 870 adult AML patients receiving standard induction therapy were detected by pyrosequencing. Associations of the mutants with responses to induction therapy and disease prognosis were analyzed.ResultsDNMT3A R882 mutations were detected in 74 (8.51%) patients and allele ratio of the mutations ranged from 6 to 50% in the cohort. After the first and second courses of induction therapy including aclarubicin, complete remission rates were significantly lower in carriers of the DNMT3A R882 mutants as compared with R882 wildtype patients (P = 0.022 and P = 0.038, respectively). Compared with R882 wild-type patients, those with the R882 mutations showed significantly shorter overall survival (OS) and disease-free survival (DFS) (P = 1.92 × 10−4 and P = 0.004, respectively). Patients with higher allele ratio of R882 mutations showed a significantly shorter OS as compared with the lower allele ratio group (P = 0.035).ConclusionOur results indicate that the impact of DNMT3A R882 mutations on AML prognosis was determined by the mutant-allele ratio and higher allele ratio could predict a worse prognosis, which might improve AML risk stratification. In addition, DNMT3A R882 mutations were associated with an inferior response to induction therapy with aclarubicin in Chinese AML patients.
Highlights
The influence of DNA methyltransferase 3 alpha (DNMT3A) arginine 882 (R882) mutations on adult acute myeloid leukemia (AML) prognosis is still con‐ troversial presently
The series of studies suggested that the allelic ratio of somatic mutations in AML could affect the biological properties of tumor and might be one of the critical factors influencing disease prognosis
In summary, DNMT3A R882 mutations were associated with a worse prognosis in Chinese AML patients, but the influence depended on DNMT3A R882 mutantallele ratio and patients with higher allele ratio had a worse prognosis
Summary
The influence of DNMT3A R882 mutations on adult acute myeloid leukemia (AML) prognosis is still con‐ troversial presently. The influence of R882 allele ratio on drug response and prognosis of AML is unknown yet. It is obscure whether anthracyclines are involved in chemoresistance resulted from R882 mutations. Acute myeloid leukemia (AML) is a clonal but heterogeneous malignancy characterized by deregulated proliferation and inhibited differentiation of hematopoietic progenitors, as well as highly diverse pathogenesis, response to chemotherapy and clinical prognosis [1]. The presence of somatic mutations in genes including NPM1 (Nucleophosmin 1), CEBPA (CCAAT/ enhancer binding protein alpha), c-KIT (tyrosine-protein kinase Kit) and FLT3 (Fms-like tyrosine kinase 3) can promote myeloid leukemogenesis and influence the prognosis of AML [3]. Disease heterogeneity may partly account for the interindividual difference in drug response and disease prognosis
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