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000144013 0247_ $$2doi$$a10.1038/s41375-019-0507-8
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000144013 0247_ $$2ISSN$$a0887-6924
000144013 0247_ $$2ISSN$$a1476-5551
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000144013 037__ $$aDKFZ-2019-01564
000144013 041__ $$aeng
000144013 082__ $$a610
000144013 1001_ $$aGiménez, Neus$$b0
000144013 245__ $$aTargeting IRAK4 disrupts inflammatory pathways and delays tumor development in chronic lymphocytic leukemia.
000144013 260__ $$aLondon$$bSpringer Nature$$c2020
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000144013 500__ $$a2020 Jan;34(1):100-114 / #EA:B060#LA:B060# / #DKFZ-MOST-Ca166#
000144013 520__ $$aInterleukin-1 receptor-associated kinase 4 (IRAK4) plays a critical role in Toll-like receptor (TLR) signal transduction and innate immune responses. Recruitment and subsequent activation of IRAK4 upon TLR stimulation is mediated by the myeloid differentiation primary response 88 (MYD88) adaptor protein. Around 3% of chronic lymphocytic leukemia (CLL) patients have activating mutations of MYD88, a driver mutation in this disease. Here, we studied the effects of TLR activation and the pharmacological inhibition of IRAK4 with ND2158, an IRAK4 competitive inhibitor, as a therapeutic approach in CLL. Our in vitro studies demonstrated that ND2158 preferentially killed CLL cells in a dose-dependent manner. We further observed a decrease in NF-κB and STAT3 signaling, cytokine secretion, proliferation and migration of primary CLL cells from MYD88-mutated and -unmutated cases. In the Eµ-TCL1 adoptive transfer mouse model of CLL, ND2158 delayed tumor progression and modulated the activity of myeloid and T cells. Our findings show the importance of TLR signaling in CLL development and suggest IRAK4 as a therapeutic target for this disease.
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000144013 7001_ $$0P:(DE-He78)cae043ee51d02e740b4c67196aa20afb$$aSchulz, Ralph$$b1$$eFirst author
000144013 7001_ $$aHigashi, Morihiro$$b2
000144013 7001_ $$aAymerich, Marta$$b3
000144013 7001_ $$00000-0001-6538-4111$$aVillamor, Neus$$b4
000144013 7001_ $$aDelgado, Julio$$b5
000144013 7001_ $$00000-0002-3064-1648$$aJuan, Manel$$b6
000144013 7001_ $$aLópez-Guerra, Mònica$$b7
000144013 7001_ $$aCampo, Elias$$b8
000144013 7001_ $$aRosich, Laia$$b9
000144013 7001_ $$0P:(DE-He78)e67f907703fcb2cf909f4d72d50268b5$$aSeiffert, Martina$$b10$$eLast author
000144013 7001_ $$00000-0001-7486-8484$$aColomer, Dolors$$b11
000144013 773__ $$0PERI:(DE-600)2008023-2$$a10.1038/s41375-019-0507-8$$n1$$p100-114$$tLeukemia$$v34$$x1476-5551$$y2020
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000144013 9141_ $$y2020
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