High frequency of additional gene mutations in acute myeloid leukemia with MLL partial tandem duplication: DNMT3A mutation is associated with poor prognosis

Abstract

The mutational profiles of acute myeloid leukemia (AML) with partial tandem duplication of mixed-lineage leukemia gene (MLL-PTD) have not been comprehensively studied. We studied 19 gene mutations for 98 patients with MLL-PTD AML to determine the mutation frequency and clinical correlations. MLL-PTD was screened by reverse-transcriptase PCR and confirmed by real-time quantitative PCR. The mutational analyses were performed with PCR-based assays followed by direct sequencing. Gene mutations of signaling pathways occurred in 63.3% of patients, with FLT3-ITD (44.9%) and FLT3-TKD (13.3%) being the most frequent. 66% of patients had gene mutations involving epigenetic regulation, and DNMT3A (32.7%), IDH2 (18.4%), TET2 (18.4%), and IDH1 (10.2%) mutations were most common. Genes of transcription pathways and tumor suppressors accounted for 23.5% and 10.2% of patients. RUNX1 mutation occurred in 23.5% of patients, while none had NPM1 or double CEBPA mutation. 90.8% of MLL-PTD AML patients had at least one additional gene mutation. Of 55 MLL-PTD AML patients who received standard chemotherapy, age older than 50 years and DNMT3A mutation were associated with inferior outcome. In conclusion, gene mutations involving DNA methylation and activated signaling pathway were common co-existed gene mutations. DNMT3A mutation was a poor prognostic factor in MLL-PTD AML.

Association between increased mutation rates in DNMT3Α and FLT3‑ITD and poor prognosis of patients with acute myeloid leukemia

“…The DNA methyltransferase 3 α (DNMT3A) gene is located on chromosome 2p23 and is highly expressed in adults (6). A recent analysis of genetic mutations in patients with AML revealed that the DNMT family of proteins is aberrantly upregulated, with the resulting hypermethylation of tumor suppressor genes a potential driver in leukemia development (7).…”

Adult acute myeloid leukemia with trisomy 11 as the sole abnormality is characterized by the presence of five distinct gene mutations: MLL-PTD, DNMT3A, U2AF1, FLT3-ITD and IDH2

“…Our findings are consistent with the recent report by Kao et al . 15 who identified co-occurring DNMT3A mutations as an unfavorable prognostic factor in AML patients harboring MLL -PTD, most of whom had a normal karyotype. However, because of the relatively small number of patients analyzed, our results concerning the prognostic impact of DNMT3A mutations in sole +11 AML are preliminary and warrant further studies.…”

DNMT3A mutants provide proliferating advantage with augmentation of self-renewal activity in the pathogenesis of AML in KMT2A-PTD-positive leukemic cells

“…Little is known about the mechanism of crosstalk and cooperation between KMT2A-PTD and other gene mutations in the leukemogenesis. We have observed a high frequency of coexistence of DNMT3A mutations with KMT2A-PTD; more importantly, it conferred a very poor outcome in our AML patients 12 . Moreover, most DNMT3A mutations (67.7%) were in the methyltransferase domain at amino acid R882 12 .…”

“…Because KMT2A-PTD alone does not generate leukemia, the acquisition of other cooperating mutations is required for leukemia transformation. Previously, using a large cohort of 98 de novo AML patients with KMT2A-PTD, we reported that 90.8% of patients had at least one additional gene mutation including FLT3-ITD (44.9%), DNMT3A (32.7%), RUNX1 (23.5%) and TET2 (18.4%) mutations 12 . We observed not only a high frequency of coexistence of DNMT3A mutations with KMT2A-PTD but also a poor outcome in patients carrying both mutations 12 .…”

“…Previously, using a large cohort of 98 de novo AML patients with KMT2A-PTD, we reported that 90.8% of patients had at least one additional gene mutation including FLT3-ITD (44.9%), DNMT3A (32.7%), RUNX1 (23.5%) and TET2 (18.4%) mutations 12 . We observed not only a high frequency of coexistence of DNMT3A mutations with KMT2A-PTD but also a poor outcome in patients carrying both mutations 12 . However, the biological functions of DNMT3A mutation in KMT2A-PTD-positive leukemia cells have not been studied before.…”