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000141404 1001_ $$aPrutsch, Nicole$$b0
000141404 245__ $$aDependency on the TYK2/STAT1/MCL1 axis in anaplastic large cell lymphoma.
000141404 260__ $$aLondon$$bSpringer Nature$$c2019
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000141404 520__ $$aTYK2 is a member of the JAK family of tyrosine kinases that is involved in chromosomal translocation-induced fusion proteins found in anaplastic large cell lymphomas (ALCL) that lack rearrangements activating the anaplastic lymphoma kinase (ALK). Here we demonstrate that TYK2 is highly expressed in all cases of human ALCL, and that in a mouse model of NPM-ALK-induced lymphoma, genetic disruption of Tyk2 delays the onset of tumors and prolongs survival of the mice. Lymphomas in this model lacking Tyk2 have reduced STAT1 and STAT3 phosphorylation and reduced expression of Mcl1, a pro-survival member of the BCL2 family. These findings in mice are mirrored in human ALCL cell lines, in which TYK2 is activated by autocrine production of IL-10 and IL-22 and by interaction with specific receptors expressed by the cells. Activated TYK2 leads to STAT1 and STAT3 phosphorylation, activated expression of MCL1 and aberrant ALCL cell survival. Moreover, TYK2 inhibitors are able to induce apoptosis in ALCL cells, regardless of the presence or absence of an ALK-fusion. Thus, TYK2 is a dependency that is required for ALCL cell survival through activation of MCL1 expression. TYK2 represents an attractive drug target due to its essential enzymatic domain, and TYK2-specific inhibitors show promise as novel targeted inhibitors for ALCL.
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000141404 7001_ $$aGurnhofer, Elisabeth$$b1
000141404 7001_ $$aSuske, Tobias$$b2
000141404 7001_ $$aLiang, Huan Chang$$b3
000141404 7001_ $$aSchlederer, Michaela$$b4
000141404 7001_ $$aRoos, Simone$$b5
000141404 7001_ $$aWu, Lawren C$$b6
000141404 7001_ $$aSimonitsch-Klupp, Ingrid$$b7
000141404 7001_ $$aAlvarez-Hernandez, Andrea$$b8
000141404 7001_ $$aKornauth, Christoph$$b9
000141404 7001_ $$aLeone, Dario A$$b10
000141404 7001_ $$aSvinka, Jasmin$$b11
000141404 7001_ $$aEferl, Robert$$b12
000141404 7001_ $$aLimberger, Tanja$$b13
000141404 7001_ $$aAufinger, Astrid$$b14
000141404 7001_ $$aShirsath, Nitesh$$b15
000141404 7001_ $$aWolf, Peter$$b16
000141404 7001_ $$0P:(DE-He78)743a4a82daab55306a2c88b9f6bf8c2f$$aHielscher, Thomas$$b17$$udkfz
000141404 7001_ $$00000-0003-2009-6305$$aAberger, Fritz$$b18
000141404 7001_ $$aSchmoellerl, Johannes$$b19
000141404 7001_ $$aStoiber, Dagmar$$b20
000141404 7001_ $$aStrobl, Birgit$$b21
000141404 7001_ $$aJäger, Ulrich$$b22
000141404 7001_ $$aStaber, Philipp B$$b23
000141404 7001_ $$00000-0003-4289-2281$$aGrebien, Florian$$b24
000141404 7001_ $$00000-0003-0918-9463$$aMoriggl, Richard$$b25
000141404 7001_ $$aMüller, Mathias$$b26
000141404 7001_ $$aInghirami, Giorgio G$$b27
000141404 7001_ $$00000-0003-1621-4954$$aSanda, Takaomi$$b28
000141404 7001_ $$aLook, A Thomas$$b29
000141404 7001_ $$aTurner, Suzanne D$$b30
000141404 7001_ $$aKenner, Lukas$$b31
000141404 7001_ $$aMerkel, Olaf$$b32
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