Aggressive natural killer-cell leukemia\xa0mutational landscape and drug profiling highlight JAK-STAT signaling as therapeutic target

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

doi:10.1038/s41467-018-03987-2

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.

Highlights

Aggressive natural killer-cell (NK-cell) leukemia (ANKL) is an extremely aggressive malignancy with dismal prognosis and lack of targeted therapies
We identified alterations in JAK-STAT, RAS-MAPK and epigenetic modifier genes as well as in DDX3X in ANKL and discovered high sensitivity of the NK lineage to JAK and BCL2 inhibition
We found JAK-STAT signaling components to be frequently altered in ANKL, with 3/14 patients harboring a STAT3 mutation

Summary

Introduction

Aggressive natural killer-cell (NK-cell) leukemia (ANKL) is an extremely aggressive malignancy with dismal prognosis and lack of targeted therapies. 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%). 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. We characterize cell lines derived from NK cell neoplasms and normal NK cells using RNA sequencing and high-throughput drug sensitivity profiling to identify therapeutically actionable drivers in malignant NK cells. We report mutations in STAT3, the RAS-mitogen-activated protein kinase (RAS-MAPK) pathway, DDX3X and epigenetic modifiers in ANKL patients and demonstrate the importance of the JAKSTAT pathway in NK cells using drug sensitivity profiling, revealing potential therapeutic targets in NK-cell malignancies

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