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.
Highlights
The mixed-lineage leukemia (MLL) gene, officially named lysine (K)-specific methyltransferase 2A (KMT2A) gene, locates on chromosome 11q23, and encodes a protein of which the SET domain has histone methyltransferase activity that methylates lysine 4 on histone H3, a modification typically associated with transcriptionally active regions of chromatin [1]
Because MLL partial tandem duplication (MLL-PTD) alone does not generate leukemia, acquisition of additional cooperating mutations is required for the development of acute myeloid leukemia (AML)
To understand the genetic background and determine whether the prognosis of MLL-PTD is influenced by any additional genetic aberration, we comprehensively investigated the pathobiologically important genetic aberrations known to be involved in myeloid neoplasms including DNA
Summary
The mixed-lineage leukemia (MLL) gene, officially named lysine (K)-specific methyltransferase 2A (KMT2A) gene, locates on chromosome 11q23, and encodes a protein of which the SET domain has histone methyltransferase activity that methylates lysine 4 on histone H3, a modification typically associated with transcriptionally active regions of chromatin [1]. MLL-PTD occurred in about 5% to 7% of adult de novo AML, mostly in patients with normal karyotypes [7,8,9,10]. Novel mutated genes involving epigenetic regulators have been described to occur recurrently in AML [12,13,14]. We examined a wide spectrum of gene mutations of epigenetic regulators, tumor suppressor genes, signal transactivation (class I) and transcription pathways (class II) on bone marrow cells from patients with de novo MLL-PTD associated AML at the initial diagnosis.
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