Journal Article

Aggressive natural killer-cell leukemia mutational landscape and drug profiling highlight JAK-STAT signaling as therapeutic target

Aittokallio, Tero, Chan, Wing C., Mustjoki, Satu, Andersson, Emma I, Kankainen, Matti, Kim, Won Seog, Awad, Shady Adnan, Kelkka, Tiina, Pietarinen, Paavo, Kovanen, Panu E., Ohshima, Koichi, Lee, Dean A., Eldfors, Samuli, Saikko, Leena, Ojala, Teija, Malani, Disha, Suzuki, Ritsuro, Ko, Young Hyeh, Chuang, Shih-Sung, Suzumiya, Junji, Loughran, Thomas P., Sekiguchi, Nodoka, Nakazawa, Hideyuki, Dufva, Olli, Yadav, Bhagwan, Kuusanmäki, Heikki, Ishida, Fumihiro

2018

Overview

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. Aggressive natural killer-cell leukemia (ANKL) has few targeted therapies. Here ANKL patients are reported to harbor STAT3, RAS-MAPK pathway, DDX3X and epigenetic modifier mutations; and drug sensitivity profiling uncovers the importance of the JAK-STAT pathway, revealing potential ANKL therapeutic targets.

• Publisher: Nature Publishing Group UK,Nature Publishing Group,Nature Portfolio
• Subject: 45/23 / 45/91 / 49/31 / 49/39 / 49/47 / 631/154/1435/2163 / 631/208/69 / 631/67/1990/283 / Adolescent / Adult / Aged / Aged, 80 and over / Child / Data processing / DEAD-box RNA Helicases - genetics / DEAD-box RNA Helicases - metabolism / Female / Gene sequencing / Genetics / Humanities and Social Sciences / Humans / Janus Kinases - genetics / Janus Kinases - metabolism / Leukemia / Leukemia, Large Granular Lymphocytic - genetics / Leukemia, Large Granular Lymphocytic - metabolism / Leukemia, Large Granular Lymphocytic - therapy / Lymphocytes T / Lymphoma / Male / Malignancy / MAP kinase / Middle Aged / multidisciplinary / Mutation / Natural killer cells / Pathogenesis / Protein-tyrosine-phosphatase / Science / Science (multidisciplinary) / Sensitivity / Signal Transduction / Signaling / Stat3 protein / STAT3 Transcription Factor - genetics / STAT3 Transcription Factor - metabolism / T-cell lymphoma / Therapeutic applications / Tyrosine / Whole Exome Sequencing / Young Adult