Oncotarget

Research Papers:

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

Hsiao-Wen Kao, Der-Cherng Liang, Ming-Chung Kuo, Jin-Hou Wu, Po Dunn, Po-Nan Wang, Tung-Liang Lin, Yu-Shu Shih, Sung-Tzu Liang, Tung-Huei Lin, Chen-Yu Lai, Chun-Hui Lin and Lee-Yung Shih _

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Oncotarget. 2015; 6:33217-33225. https://doi.org/10.18632/oncotarget.5202

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Abstract

Hsiao-Wen Kao1,2, Der-Cherng Liang3, Ming-Chung Kuo1,4, Jin-Hou Wu1, Po Dunn1,4, Po-Nan Wang1, Tung-Liang Lin1, Yu-Shu Shih1, Sung-Tzu Liang3, Tung-Huei Lin1, Chen-Yu Lai4, Chun-Hui Lin3, Lee-Yung Shih1,4

1Division of Hematology-Oncology, Department of Internal Medicine, Chang Gung Memorial Hospital at Linkou, Taoyuan, Taiwan

2Graduate Institute of Clinical Medical Sciences, College of Medicine, Chang Gung University, Taoyuan, Taiwan

3Division of Pediatric Hematology-Oncology, Mackay Memorial Hospital, Taipei, Taiwan

4College of Medicine, Chang Gung University, Taoyuan, Taiwan

Correspondence to:

Lee-Yung Shih, e-mail: sly7012@adm.cgmh.org.tw

Keywords: MLL-PTD, acute myeloid leukemia, gene mutation, DNMT3A mutation

Received: July 30, 2015     Accepted: August 28, 2015     Published: September 08, 2015

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.


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