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DOI | 10.1038/s41467-018-02901-0 |
Aggressive natural killer-cell leukemia mutational landscape and drug profiling highlight JAK-STAT signaling as therapeutic target | |
Dufva, Olli1,2; Kankainen, Matti3,4,5; Kelkka, Tiina1,2; Sekiguchi, Nodoka6; Awad, Shady Adnan1,2; Eldfors, Samuli3; Yadav, Bhagwan1,2; Kuusanmaki, Heikki1,2,3; Malani, Disha3; Andersson, Emma I.1,2; Pietarinen, Paavo1,2; Saikko, Leena5,7,8; Kovanen, Panu E.5,7,8; Ojala, Teija9; Lee, Dean A.10; Loughran, Thomas P., Jr.11; Nakazawa, Hideyuki12; Suzumiya, Junji13; Suzuki, Ritsuro13; Ko, Young Hyeh14; Kim, Won Seog15; Chuang, Shih-Sung16; Aittokallio, Tero; Chan, Wing C.17; Ohshima, Koichi18; Ishida, Fumihiro19; Mustjoki, Satu1,2,20 | |
2018-04-19 | |
发表期刊 | NATURE COMMUNICATIONS |
ISSN | 2041-1723 |
出版年 | 2018 |
卷号 | 9 |
文章类型 | Article |
语种 | 英语 |
国家 | Finland; Japan; USA; South Korea; Taiwan |
英文摘要 | Aggressive natural killer-cell (NK-cell) leukemia (ANKL) is an extremely aggressive malignancy with dismal prognosis and lack of targeted therapies. Here, we elucidate the molecular pathogenesis of ANKL using a combination of genomic and drug sensitivity profiling. We study 14 ANKL patients using whole-exome sequencing (WES) and identify mutations in STAT3 (21%) and RAS-MAPK pathway genes (21%) as well as in DDX3X (29%) and epigenetic modifiers (50%). Additional alterations include JAK-STAT copy gains and tyrosine phosphatase mutations, which we show recurrent also in extranodal NK/T-cell lymphoma, nasal type (NKTCL) through integration of public genomic data. Drug sensitivity profiling further demonstrates the role of the JAK-STAT pathway in the pathogenesis of NK-cell malignancies, identifying NK cells to be highly sensitive to JAK and BCL2 inhibition compared to other hematopoietic cell lineages. Our results provide insight into ANKL genetics and a framework for application of targeted therapies in NK-cell malignancies. |
领域 | 资源环境 |
收录类别 | SCI-E |
WOS记录号 | WOS:000430389400002 |
WOS关键词 | DIFFERENTIAL EXPRESSION ANALYSIS ; GAMMA-DELTA-T ; LYMPHOPROLIFERATIVE DISORDERS ; LYMPHOMA ; LINE ; RECEPTOR ; PHOSPHATASE ; NEOPLASMS ; CANCER ; GENE |
WOS类目 | Multidisciplinary Sciences |
WOS研究方向 | Science & Technology - Other Topics |
URL | 查看原文 |
引用统计 | |
文献类型 | 期刊论文 |
条目标识符 | http://119.78.100.173/C666/handle/2XK7JSWQ/203661 |
专题 | 资源环境科学 |
作者单位 | 1.Univ Helsinki, Hematol Res Unit Helsinki, FIN-00290 Helsinki, Finland; 2.Helsinki Univ Hosp, Comprehens Canc Ctr, Dept Hematol, FIN-00290 Helsinki, Finland; 3.Univ Helsinki, Inst Mol Med Finland FIMM, FIN-00014 Helsinki, Finland; 4.Univ Helsinki, Med & Clin Genet, FIN-00290 Helsinki, Finland; 5.Helsinki Univ Hosp, FIN-00290 Helsinki, Finland; 6.Shinshu Univ, Sch Med, Dept Comprehens Canc Therapy, Matsumoto, Nagano 3908621, Japan; 7.Univ Helsinki, HUSLAB, Dept Pathol, FIN-00290 Helsinki, Finland; 8.Univ Helsinki, Haartman Inst, FIN-00290 Helsinki, Finland; 9.Univ Helsinki, Fac Med, Pharmacol, FIN-00014 Helsinki, Finland; 10.Nationwide Childrens Hosp, Div Hematol Oncol & BMT, Columbus, OH 43205 USA; 11.Univ Virginia, Dept Med, Charlottesville, VA 22908 USA; 12.Shinshu Univ, Sch Med, Div Hematol, Internal Med, Matsumoto, Nagano 3908621, Japan; 13.Shimane Univ Hosp, Dept Oncol Hematol, Izumo, Shimane 6938501, Japan; 14.Samsung Med Ctr, Dept Pathol, Seoul 0635, South Korea; 15.Sungkyunkwan Univ, Sch Med, Samsung Med Ctr, Seoul 0635, South Korea; 16.Chi Mei Med Ctr, Dept Pathol, Tainan 71004, Taiwan; 17.City Hope Natl Med Ctr, Dept Pathol, Duarte, CA 91010 USA; 18.Kurume Univ, Sch Med, Dept Pathol, Kurume, Fukuoka 8300011, Japan; 19.Shinshu Univ, Sch Med, Dept Biomed Lab Sci, Matsumoto, Nagano 3908621, Japan; 20.Univ Helsinki, Dept Clin Chem, FIN-00014 Helsinki, Finland |
推荐引用方式 GB/T 7714 | Dufva, Olli,Kankainen, Matti,Kelkka, Tiina,et al. Aggressive natural killer-cell leukemia mutational landscape and drug profiling highlight JAK-STAT signaling as therapeutic target[J]. NATURE COMMUNICATIONS,2018,9. |
APA | Dufva, Olli.,Kankainen, Matti.,Kelkka, Tiina.,Sekiguchi, Nodoka.,Awad, Shady Adnan.,...&Mustjoki, Satu.(2018).Aggressive natural killer-cell leukemia mutational landscape and drug profiling highlight JAK-STAT signaling as therapeutic target.NATURE COMMUNICATIONS,9. |
MLA | Dufva, Olli,et al."Aggressive natural killer-cell leukemia mutational landscape and drug profiling highlight JAK-STAT signaling as therapeutic target".NATURE COMMUNICATIONS 9(2018). |
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