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

Author

Listed:
  • Olli Dufva

    (Helsinki University Hospital Comprehensive Cancer Center)

  • Matti Kankainen

    (University of Helsinki
    University of Helsinki and Helsinki University Hospital)

  • 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
    University of Helsinki)

  • 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
    University of Helsinki)

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.

Suggested Citation

  • 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 Saik, 2018. "Aggressive natural killer-cell leukemia mutational landscape and drug profiling highlight JAK-STAT signaling as therapeutic target," Nature Communications, Nature, vol. 9(1), pages 1-12, December.
    • Handle: RePEc:nat:natcom:v:9:y:2018:i:1:d:10.1038_s41467-018-03987-2
    DOI: 10.1038/s41467-018-03987-2
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