NRASmutDNMT3Amut Clone Identifies a Subset of de novo Cytogenetically Normal Acute Myeloid Leukemia with Adverse Prognosis.

To investigate the molecular characteristics and clinical prognosis of the neuroblastoma RAS viral oncogene (NRAS) in patients with primary cytogenetically normal acute myeloid leukemia (AML).A total of 171 adult patients with cytogenetically normal primary AML were collected, and 34 gene mutations in these patients were detected by targeted next-generation sequencing.Among 171 patients with cytogenetically normal AML(CN-AML), 17 (9.9%) patients had found NRAS mutations. Among the 17 NRAS mutant patients, 16 cases were associated with the concomitant gene, and NRAS mutation (NRASmut) was significantly positively correlated with DNMT3A mutation (DNMT3Amut) (P=0.011) and KRAS mutation (P=0.008) compared with the NRAS wild-type (NRASwt) group. The frequency of NRASmutDNMT3Amut clone was significantly higher in CN-AML patients with NRAS mutation (8/17, 47%). The total NRASmut group showed no significant differences on clinical characteristics, CR rate after induction therapy, OS, and RFS as compared with NRASwt group. However, patients with NRASmutDNMT3Amut provided a shorter effect on OS (median:7 vs 15 months; P=0.036) and RFS (median: 3 vs 12 months; P=0.003) than those with NRASwt, though no statistic differences on demographics, lab parameters, treatment and CR rate of patients receiving induction therapy. Multivariate analysis showed that NRASmutDNMT3Amut subtype could independently affect the RFS of CN-AML patients (HR:3.210, 95%CI:1.078-9.557, P=0.036).NRASmutDNMT3Amut clones have a high frequency of occurrence and show a poor survival prognosis. Our findings highlight potentially novel aspects of the underlying biology of NRASmutDNMT3Amut commutation in adult de novo CN-AML.