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

Olli Dufva, Matti Kankainen, Tiina Kelkka, Nodoka Sekiguchi, Shady Adnan Awad, Samuli Eldfors, Bhagwan Yadav, Heikki Kuusanmäki, Disha Malani, Emma I Andersson, Paavo Pietarinen, Leena Saikko, Panu E. Kovanen, Teija Ojala, Dean A. Lee, Thomas P. Loughran, Hideyuki Nakazawa, Junji Suzumiya, Ritsuro Suzuki, Young Hyeh Ko, Won Seog Kim, Shih-Sung Chuang, Tero Aittokallio, Wing C. Chan, Koichi Ohshima, Fumihiro Ishida and Satu Mustjoki ()
Additional contact information
Olli Dufva: Helsinki University Hospital Comprehensive Cancer Center
Matti Kankainen: University of Helsinki
Tiina Kelkka: Helsinki University Hospital Comprehensive Cancer Center
Nodoka Sekiguchi: Shinshu University School of Medicine
Shady Adnan Awad: Helsinki University Hospital Comprehensive Cancer Center
Samuli Eldfors: University of Helsinki
Bhagwan Yadav: Helsinki University Hospital Comprehensive Cancer Center
Heikki Kuusanmäki: Helsinki University Hospital Comprehensive Cancer Center
Disha Malani: University of Helsinki
Emma I Andersson: Helsinki University Hospital Comprehensive Cancer Center
Paavo Pietarinen: Helsinki University Hospital Comprehensive Cancer Center
Leena Saikko: University of Helsinki and Helsinki University Hospital
Panu E. Kovanen: University of Helsinki and Helsinki University Hospital
Teija Ojala: University of Helsinki
Dean A. Lee: Oncology, and BMT
Thomas P. Loughran: University of Virginia
Hideyuki Nakazawa: Shinshu University School of Medicine
Junji Suzumiya: Shimane University Hospital
Ritsuro Suzuki: Shimane University Hospital
Young Hyeh Ko: Samsung Medical Center
Won Seog Kim: Samsung Medical Center
Shih-Sung Chuang: Chi-Mei Medical Center
Tero Aittokallio: University of Helsinki
Wing C. Chan: City of Hope National Medical Center
Koichi Ohshima: Kurume University School of Medicine
Fumihiro Ishida: Shinshu University School of Medicine
Satu Mustjoki: Helsinki University Hospital Comprehensive Cancer Center

Nature Communications, 2018, vol. 9, issue 1, 1-12

Abstract: Abstract 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.

Date: 2018
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DOI: 10.1038/s41467-018-03987-2

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