Integrated molecular analysis of adult T cell leukemia/lymphoma.
Keisuke KataokaYasunobu NagataAkira KitanakaYuichi ShiraishiTeppei ShimamuraJun-Ichirou YasunagaYasushi TotokiKenichi ChibaAiko Sato-OtsuboGenta NagaeRyohei IshiiSatsuki MutoShinichi KotaniYosaku WatataniJune TakedaMasashi SanadaHiroko TanakaHiromichi SuzukiYusuke SatoYusuke ShiozawaTetsuichi YoshizatoKenichi YoshidaHideki MakishimaMasako IwanagaGuangyong MaKisato NosakaMasakatsu HishizawaHidehiro ItonagaYoshitaka ImaizumiWataru MunakataHideaki OgasawaraToshitaka SatoKen SasaiKenzo MuramotoMarina PenovaTakahisa KawaguchiHiromi NakamuraNatsuko HamaKotaro ShideYoko KubukiTomonori HidakaTakuro KamedaTsuyoshi NakamakiKen IshiyamaShuichi MiyawakiSung-Soo YoonKensei TobinaiYasushi MiyazakiAkifumi Takaori-KondoFumihiko MatsudaKengo TakeuchiOsamu NurekiHiroyuki AburataniToshiki WatanabeTatsuhiro ShibataMasao MatsuokaSatoru MiyanoKazuya ShimodaSeishi OgawaPublished in: Nature genetics (2015)
Adult T cell leukemia/lymphoma (ATL) is a peripheral T cell neoplasm of largely unknown genetic basis, associated with human T cell leukemia virus type-1 (HTLV-1) infection. Here we describe an integrated molecular study in which we performed whole-genome, exome, transcriptome and targeted resequencing, as well as array-based copy number and methylation analyses, in a total of 426 ATL cases. The identified alterations overlap significantly with the HTLV-1 Tax interactome and are highly enriched for T cell receptor-NF-κB signaling, T cell trafficking and other T cell-related pathways as well as immunosurveillance. Other notable features include a predominance of activating mutations (in PLCG1, PRKCB, CARD11, VAV1, IRF4, FYN, CCR4 and CCR7) and gene fusions (CTLA4-CD28 and ICOS-CD28). We also discovered frequent intragenic deletions involving IKZF2, CARD11 and TP73 and mutations in GATA3, HNRNPA2B1, GPR183, CSNK2A1, CSNK2B and CSNK1A1. Our findings not only provide unique insights into key molecules in T cell signaling but will also guide the development of new diagnostics and therapeutics in this intractable tumor.
Keyphrases
- copy number
- genome wide
- mitochondrial dna
- acute myeloid leukemia
- dna methylation
- bone marrow
- dendritic cells
- signaling pathway
- diffuse large b cell lymphoma
- endothelial cells
- acute lymphoblastic leukemia
- regulatory t cells
- gene expression
- oxidative stress
- transcription factor
- high resolution
- nk cells
- pi k akt
- high throughput
- fatty acid
- drug delivery
- low grade
- single molecule
- childhood cancer
- inflammatory response
- immune response
- lps induced