DNMT3A mutations in acute myeloid leukemia: stability during disease evolution and clinical implications

Abstract

DNMT3A mutations are associated with poor prognosis in acute myeloid leukemia (AML), but the stability of this mutation during the clinical course remains unclear. In the present study of 500 patients with de novo AML, DNMT3A mutations were identified in 14% of total patients and in 22.9% of AML patients with normal karyotype. DNMT3A mutations were positively associated with older age, higher WBC and platelet counts, intermediate-risk and normal cytogenetics, FLT3 internal tandem duplication, and NPM1, PTPN11, and IDH2 mutations, but were negatively associated with CEBPA mutations. Multivariate analysis demonstrated that the DNMT3A mutation was an independent poor prognostic factor for overall survival and relapse-free survival in total patients and also in normokaryotype group. A scoring system incorporating the DNMT3A mutation and 8 other prognostic factors, including age, WBC count, cytogenetics, and gene mutations, into survival analysis was very useful in stratifying AML patients into different prognostic groups (P < .001). Sequential study of 138 patients during the clinical course showed that DNMT3A mutations were stable during AML evolution. In conclusion, DNMT3A mutations are associated with distinct clinical and biologic features and poor prognosis in de novo AML patients. Furthermore, the DNMT3A mutation may be a potential biomarker for monitoring of minimal residual disease. (Blood. 2012;119(2):559-568)

Prognostic significance of DNA methyltransferase 3A mutations in cytogenetically normal acute myeloid leukemia: a study by the Acute Leukemia French Association

“…We and others 24,25,29 --31,44 found that DNMT3A mutations were strongly associated with FAB M4/M5 subtypes, and often co-occurred with NPM1 or IDH1 mutations in AML patients, suggesting that the oncogenic actions of these mutations are not redundant. DNMT3A mutations were reported to be associated with older age, 24,25,30,31 but this feature was not observed in our cohort of adult CN-AML. Nevertheless, a link between age and the incidence of DNMT3A mutations is likely as these mutations seem to be extremely rare (o1%) in pediatric AML.…”

“…Factors related to patient and disease characteristics, and differences in treatment modalities may account for these different findings, but the exact reasons for this discordance remain unknown. DNMT3A mutations rarely occur in patients with CEBPA mutations, 30 especially in those with double CEBPA mutations, 51 and the clinical outcome of AML patients who carry both mutations is yet uncertain. 51 In our cohort, the prognostic impact of DNMT3A mutations in patients with CEBPA mutations was not evaluable, as CEBPA and DNMT3A mutations were mutually exclusive.…”

The de novo DNA methyltransferase DNMT3A in development and cancer

“…89 Although previous studies clearly pointed to an oncogenic role of DNMT3A in cancer, the recent discovery of genetic mutations of DNMT3A in acute myeloid leukemia (AML) suggested that its role in cancers may be more complex than was previously believed. [11][12][13][14][15][16][17][18][19][20][21][22][23] These highly recurrent DNMT3A mutations were closely associated with poor outcome in patients with AML. However, the functional implications of these mutations are still poorly understood.…”

“…10 However, several inactivating mutations of DNMT3A in myeloid malignancies [11][12][13][14][15][16][17][18][19][20][21][22][23] and loss of DNMT3A activity at advanced tumor stages 24 were recently identified. In addition, novel roles of DNMT3A in the hematopoiesis system 25 and in the age-related decline of cognition 26 have been revealed.…”

Comparable outcomes between autologous and allogeneic transplant for adult acute myeloid leukemia in first CR

“…180,181 Similarly, the DMNT3A mutation is found at a higher percentage in adult (15%-20%) compared to childhood (2%) AML. 63,182,183 The FLT3-ITD mutation is found in 25% of adult and 15% of childhood AML. 43,184 Two less well-studied mutations that may serve as MRD markers include CEBPA and MLLpartial tandem duplications.…”