DNMT3A and IDH1/2 Mutations Are Stable During the Progression of Acute Myeloid Leukemia

Abstract 1466

Several genetic alterations, which are involved in the pathophysiology of acute myeloid leukemia (AML), have been identified. Recently some mutations in genes affecting DNA and histone methylation have been reported. Their stabilities during the disease progression are not fully clarified. We analyzed mutations of FLT3, NRAS, NPM1, TP53, CEBPA, IDH1/2 and DNMT3A genes in paired initial diagnosis and the first relapse samples from 44 adult AML patients. Informed consent was obtained from all patients, and approval was obtained from the ethics committee of Nagoya university school of medicine. At diagnosis, we identified FLT3 mutation in 12 patients, NPM1 mutation in 17, N-RAS mutation in 7, TP53 mutation in 2, CEBPA mutation in 7, IDH1/2 mutations in 10 and DNMT3A mutation in 6. At relapse, the acquisition and loss of FLT3 mutation were observed in 4 and 1 patients, respectively. Those of N-RAS mutation were in 2 and 3 patients, respectively, and those of TP53 mutation were in each one. No patient acquired NPM1 mutation, but one patient lost it at relapse. And no patient acquired CEBPA mutation, but 2 patients lost it at relapse. One patient acquired IDH1/2 mutation, but no patient lost them at relapse. The acquisition and loss of DNMT3A mutation was not observed. Notably, one patient harboring IDH1 and FLT3 mutations at the diagnosis lost FLT3 mutation, but not IDH1 mutation at relapse; one patient harboring IDH1, DNMT3A and NRAS mutations at the diagnosis lost NRAS mutation, but not IDH1 and DNMT3A mutations at relapse and one patient harboring IDH2 and CEBPA mutations at the diagnosis lost CEBPA mutation, but not IDH2 mutation at relapse. These results indicated that Class 2 mutation, which is more stable than Class 1 mutations, may be lost during the progression of AML. However, IDH1/2 and DNMT3A mutations were stable during the disease course of AML suggesting aberrations of the DNA methylation is an early event in the leukemogenesis.

Table Frequencies of gain and loss of gene mutations at relapse in AML