Frequency, onset and clinical impact of somatic DNMT3A mutations in therapy-related and secondary acute myeloid leukemia

Abstract

The recent identification of DNMT3A mutations in de novo acute myeloid leukemia prompted us to determine their frequency, patterns and clinical impact in a cohort of 98 patients with either therapy-related or secondary acute myeloid leukemia developing from an antecedent hematologic disorder. We identified 24 somatic mutations in 23 patients with a significantly higher frequency in secondary acute myeloid leukemia (35.1%) as compared to therapy-related acute myeloid leukemia (16.4%, P=0.0486). DNMT3A mutations were associated with a normal karyotype and IDH1/2 mutations, but did not affect survival. In contrast to de novo acute myeloid leukemia, most mutations did not affect arginine on position 882, but were predominantly found in the methyltransferase domain. All DNMT3A mutations identified in secondary acute myeloid leukemia were already present in the antecedent disorders indicating an early event. Reduction to homozygosity by uniparental disomy was observed in 2 patients with secondary acute myeloid leukemia during disease progression.

Figure 1.

Uniparental disomy of 2p23.3 results in homozygous DNMT3A mutations in distinct t-AML and sAML patients. (A) Electropherograms of two homozygous DNMT3A mutations in t-AML samples showing no mutation in the corresponding constitutional material. SNP-array analysis revealed a copy-neutral loss of heterozygosity of 2p11-2pter that harbors the DNMT3A gene locus in both t-AML samples. (B) Electro-pherograms of one patient (upper panel) with a somatic heterozygous mutation in MDS who developed a homozygous W795C mutation during the progression to sAML. A second patient (lower panel) showed a somatic heterozygous mutation at sAML diagnosis, but displayed a homozygous F752L mutation at the time of sAML relapse after autologous stem cell transplantation. Corresponding SNP-array analysis demonstrated a copy-neutral loss of heterozygosity of 2p23.3-2pter in both samples with the homozygous mutations, but not in the samples with heterozygous DNMT3A mutations. c: constitutional material; LOH: loss of heterozygosity; CN: copy number; Chr2p: short arm of chromosome 2.

Figure 2.

Survival analysis of 82 t-AML and sAML patients with respect to their DNMT3A mutational status. (A) The overall survival of t-AML patients with DNMT3A mutations (n=7) as compared to non-mutated patients (n=42). (B) The overall survival of sAML patients with DNMT3A mutations (n=13) as compared to patients without DNMT3A mutations (n=20). (C) Kaplan-Meier plot of time to progression to sAML with respect to the DNMT3A mutation status in patients diagnosed with MDS/MPN.