title: 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.
authors.affiliation: Division of Hematology-Oncology, Department of Internal Medicine, Chang Gung Memorial Hospital at Linkou, Taoyuan, Taiwan.|Graduate Institute of Clinical Medical Sciences, College of Medicine, Chang Gung University, Taoyuan, Taiwan.
authors.forename: Hsiao-Wen
authors.initials: HW
authors.lastname: Kao
authors.affiliation: Division of Pediatric Hematology-Oncology, Mackay Memorial Hospital, Taipei, Taiwan.
authors.forename: D Cherng
authors.initials: DC
authors.lastname: Liang
authors.affiliation: Division of Hematology-Oncology, Department of Internal Medicine, Chang Gung Memorial Hospital at Linkou, Taoyuan, Taiwan.|College of Medicine, Chang Gung University, Taoyuan, Taiwan.
authors.forename: Ming-Chung
authors.initials: MC
authors.lastname: Kuo
authors.affiliation: Division of Hematology-Oncology, Department of Internal Medicine, Chang Gung Memorial Hospital at Linkou, Taoyuan, Taiwan.
authors.forename: Jin-Hou
authors.initials: JH
authors.lastname: Wu
authors.affiliation: Division of Hematology-Oncology, Department of Internal Medicine, Chang Gung Memorial Hospital at Linkou, Taoyuan, Taiwan.|College of Medicine, Chang Gung University, Taoyuan, Taiwan.
authors.forename: Po
authors.initials: P
authors.lastname: Dunn
authors.affiliation: Division of Hematology-Oncology, Department of Internal Medicine, Chang Gung Memorial Hospital at Linkou, Taoyuan, Taiwan.
authors.forename: Po-Nan
authors.initials: PN
authors.lastname: Wang
authors.affiliation: Division of Hematology-Oncology, Department of Internal Medicine, Chang Gung Memorial Hospital at Linkou, Taoyuan, Taiwan.
authors.forename: Tung-Liang
authors.initials: TL
authors.lastname: Lin
authors.affiliation: Division of Hematology-Oncology, Department of Internal Medicine, Chang Gung Memorial Hospital at Linkou, Taoyuan, Taiwan.
authors.forename: Yu-Shu
authors.initials: YS
authors.lastname: Shih
authors.affiliation: Division of Pediatric Hematology-Oncology, Mackay Memorial Hospital, Taipei, Taiwan.
authors.forename: Sung-Tzu
authors.initials: ST
authors.lastname: Liang
authors.affiliation: Division of Hematology-Oncology, Department of Internal Medicine, Chang Gung Memorial Hospital at Linkou, Taoyuan, Taiwan.
authors.forename: Tung-Huei
authors.initials: TH
authors.lastname: Lin
authors.affiliation: College of Medicine, Chang Gung University, Taoyuan, Taiwan.
authors.forename: Chen-Yu
authors.initials: CY
authors.lastname: Lai
authors.affiliation: Division of Pediatric Hematology-Oncology, Mackay Memorial Hospital, Taipei, Taiwan.
authors.forename: Chun-Hui
authors.initials: CH
authors.lastname: Lin
authors.affiliation: Division of Hematology-Oncology, Department of Internal Medicine, Chang Gung Memorial Hospital at Linkou, Taoyuan, Taiwan.|College of Medicine, Chang Gung University, Taoyuan, Taiwan.
authors.forename: Lee-Yung
authors.initials: LY
authors.lastname: Shih
mesh_terms: D000293:Adolescent; D000328:Adult; D000368:Aged; D000369:Aged, 80 and over; D002648:Child; D004248:DNA (Cytosine-5-)-Methyltransferases / Q000235:genetics*; D000090205:DNA Methyltransferase 3A; D005260:Female; D020440:Gene Duplication; D005787:Gene Frequency; D011495:Histone-Lysine N-Methyltransferase / Q000235:genetics*; D006801:Humans; D015470:Leukemia, Myeloid, Acute / Q000175:diagnosis* / Q000235:genetics* / Q000401:mortality; D008297:Male; D008875:Middle Aged; D009154:Mutation; D051788:Myeloid-Lymphoid Leukemia Protein / Q000235:genetics*; D000090243:Nucleophosmin; D011379:Prognosis; D016019:Survival Analysis; D020080:Tandem Repeat Sequences; D055815:Young Adult
chemical_list: C000717967:DNMT3A protein, human; C497422:KMT2A protein, human; C000716967:NPM1 protein, human; D000090243:Nucleophosmin; D051788:Myeloid-Lymphoid Leukemia Protein; D004248:DNA (Cytosine-5-)-Methyltransferases; D000090205:DNA Methyltransferase 3A; D011495:Histone-Lysine N-Methyltransferase
keywords: DNMT3A mutation; MLL-PTD; acute myeloid leukemia; gene mutation