A1 Refereed original research article in a scientific journal
Aggressive natural killer-cell leukemia mutational landscape and drug profiling highlight JAK-STAT signaling as therapeutic target
Authors: Dufva O, Kankainen M, Kelkka T, Sekiguchi N, Awad SA, Eldfors S, Yadav B, Kuusanmaki H, Malani D, Andersson EI, Pietarinen P, Saikko L, Kovanen PE, Ojala T, Lee DA, Loughran TP, Nakazawa H, Suzumiya J, Suzuki R, Ko YH, Kim WS, Chuang SS, Aittokallio T, Chan WC, Ohshima K, Ishida F, Mustjoki S, Mustjoki S
Publisher: NATURE PUBLISHING GROUP
Publication year: 2018
Journal: Nature Communications
Journal name in source: NATURE COMMUNICATIONS
Journal acronym: NAT COMMUN
Article number: ARTN 1567
Volume: 9
Number of pages: 12
ISSN: 2041-1723
DOI: https://doi.org/10.1038/s41467-018-03987-2
Self-archived copy’s web address: https://research.utu.fi/converis/portal/Publication/32840822
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.
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