Nature communications · 2018
Aggressive natural killer-cell leukemia mutational landscape and drug profiling highlight JAK-STAT signaling as therapeutic target.
СтатьяПоддержка исследования: вне правительства СШАНазвание и аннотация: Перевод пока не подготовлен
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Dufva Olli, Kankainen Matti, Kelkka Tiina, Sekiguchi Nodoka, Awad Shady Adnan, Eldfors Samuli, Yadav Bhagwan, Kuusanmäki Heikki, Malani Disha, Andersson Emma I, Pietarinen Paavo, Saikko Leena, Kovanen Panu E, Ojala Teija, Lee Dean A, Loughran Thomas P, Nakazawa Hideyuki, Suzumiya Junji, Suzuki Ritsuro, Ko Young Hyeh, Kim Won Seog, Chuang Shih-Sung, Aittokallio Tero, Chan Wing C, Ohshima Koichi, Ishida Fumihiro, Mustjoki Satu
Аннотация
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.