Mutation of epigenetic regulators TET2 and MLL3 in patients with HTLV-I-induced acute adult T-cell leukemia

Molecular Cancer

Research

Toshiki Watanabe¹  Lee Ratner²  Christophe Nicot³  Chien-Hung Yeh³  Ramona Moles³  Xue Tao Bai³  Thomas A. Waldmann⁴ 

[1] Department of Medical Genome Sciences, University of Tokyo, Tokyo, Japan;Department of Medicine, Division of Molecular Oncology, Washington University School of Medicine, 63110, Saint Louis, MO, USA;Department of Pathology, Center for Viral Oncology, University of Kansas Medical Center, 3901 Rainbow Boulevard, 66160, Kansas City, KS, USA;Lymphoid Malignancies Branch, Center for Cancer Research, National Institutes of Health, Building 10, Room 4 N/115, 10 Center Drive, 20892, Bethesda, MD, USA;

关键词: HTLV-I;    Leukemia;    ATL;    LOH;    TET2;    MLL3;    Epigenetic;   

DOI  :  10.1186/s12943-016-0500-z

 received in 2015-10-17, accepted in 2016-02-11,  发布年份 2016

来源: Springer

【 摘 要 】

BackgroundEpigenetic regulators play a critical role in the maintenance of specific chromatin domains in an active or repressed state. Disruption of epigenetic regulatory mechanisms is widespread in cancer cells and largely contributes to the transformation process through active repression of tumor suppressor genes. While mutations of epigenetic regulators have been reported in various lymphoid malignancies and solid cancers, mutation of these genes in HTLV-I-associated T-cell leukemia has not been investigated.MethodHere we used whole genome next generation sequencing (NGS) of uncultured freshly isolated ATL samples and identified the presence of mutations in SUZ12, DNMT1, DNMT3A, DNMT3B, TET1, TET2, IDH1, IDH2, MLL, MLL2, MLL3 and MLL4.ResultsTET2 was the most frequently mutated gene, occurring in 32 % (10/31) of ATL samples analyzed. Interestingly, NGS revealed nonsense mutations accompanied by loss of heterozygosity (LOH) in TET2 and MLL3, which was further confirmed by cloning and direct sequencing of DNA from uncultured cells. Finally, direct sequencing of matched control and tumor samples revealed that TET2 mutation was present only in ATL tumor cells.ConclusionsOur results suggest that inactivation of MLL3 and TET2 may play an important role in the tumorigenesis process of HTLV-I-induced ATL.

【 授权许可】

CC BY   
© Yeh et al. 2016