Browsing by Subject "LYMPHOPROLIFERATIVE DISORDERS"

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  • Dufva, Olli; Kankainen, Matti; Kelkka, Tiina; Sekiguchi, Nodoka; Awad, Shady Adnan; Eldfors, Samuli; Yadav, Bhagwan; Kuusanmäki, Heikki; Malani, Disha; Andersson, Emma I.; Pietarinen, Paavo; Saikko, Leena; Kovanen, Panu E.; Ojala, Teija; Lee, Dean A.; Loughran, Thomas P.; Nakazawa, Hideyuki; Suzumiya, Junji; Suzuki, Ritsuro; Ko, Young Hyeh; Kim, Won Seog; Chuang, Shih-Sung; Aittokallio, Tero; Chan, Wing C.; Ohshima, Koichi; Ishida, Fumihiro; Mustjoki, Satu (2018)
    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.
  • Parri, Elina; Kuusanmäki, Heikki; van Adrichem, Arjan J.; Kaustio, Meri; Wennerberg, Krister (2020)
    STAT3 mediates signalling downstream of cytokine and growth factor receptors where it acts as a transcription factor for its target genes, including oncogenes and cell survival regulating genes. STAT3 has been found to be persistently activated in many types of cancers, primarily through its tyrosine phosphorylation (Y705). Here, we show that constitutive STAT3 activation protects cells from cytotoxic drug responses of several drug classes. To find novel and potentially targetable STAT3 regulators we performed a kinase and phosphatase siRNA screen with cells expressing either a hyperactive STAT3 mutant or IL6-induced wild type STAT3. The screen identified cell division cycle 7-related protein kinase (CDC7), casein kinase 2, alpha 1 (CSNK2), discoidin domain-containing receptor 2 (DDR2), cyclin-dependent kinase 8 (CDK8), phosphatidylinositol 4-kinase 2-alpha (PI4KII), C-terminal Src kinase (CSK) and receptor-type tyrosine-protein phosphatase H (PTPRH) as potential STAT3 regulators. Using small molecule inhibitors targeting these proteins, we confirmed dose and time dependent inhibition of STAT3-mediated transcription, suggesting that inhibition of these kinases may provide strategies for dampening STAT3 activity in cancers.