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000131777 1001_ $$0P:(DE-He78)6333b389d0abc96ef7f2f6e049a8f8c4$$aDietrich, Sascha$$b0$$eFirst author
000131777 245__ $$aDrug-perturbation-based stratification of blood cancer.
000131777 260__ $$aAnn Arbor, Mich.$$bASCJ$$c2018
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000131777 520__ $$aAs new generations of targeted therapies emerge and tumor genome sequencing discovers increasingly comprehensive mutation repertoires, the functional relationships of mutations to tumor phenotypes remain largely unknown. Here, we measured ex vivo sensitivity of 246 blood cancers to 63 drugs alongside genome, transcriptome, and DNA methylome analysis to understand determinants of drug response. We assembled a primary blood cancer cell encyclopedia data set that revealed disease-specific sensitivities for each cancer. Within chronic lymphocytic leukemia (CLL), responses to 62% of drugs were associated with 2 or more mutations, and linked the B cell receptor (BCR) pathway to trisomy 12, an important driver of CLL. Based on drug responses, the disease could be organized into phenotypic subgroups characterized by exploitable dependencies on BCR, mTOR, or MEK signaling and associated with mutations, gene expression, and DNA methylation. Fourteen percent of CLLs were driven by mTOR signaling in a non-BCR-dependent manner. Multivariate modeling revealed immunoglobulin heavy chain variable gene (IGHV) mutation status and trisomy 12 as the most important modulators of response to kinase inhibitors in CLL. Ex vivo drug responses were associated with outcome. This study overcomes the perception that most mutations do not influence drug response of cancer, and points to an updated approach to understanding tumor biology, with implications for biomarker discovery and cancer care.
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000131777 7001_ $$aOleś, Małgorzata$$b1
000131777 7001_ $$aLu, Junyan$$b2
000131777 7001_ $$0P:(DE-He78)b07a76205b49e86733668b7201520d19$$aSellner, Leopold$$b3
000131777 7001_ $$aAnders, Simon$$b4
000131777 7001_ $$aVelten, Britta$$b5
000131777 7001_ $$0P:(DE-He78)f385b8b832d53e921e7af2af3c625418$$aWu, Bian$$b6
000131777 7001_ $$0P:(DE-He78)c9be4ab60d1090c3d315a2ca6905e9ea$$aHüllein, Jennifer$$b7
000131777 7001_ $$0P:(DE-HGF)0$$ada Silva Liberio, Michelle$$b8
000131777 7001_ $$0P:(DE-He78)e8feda17d03b95bda3e8717e79dc07b8$$aWalther, Tatjana$$b9
000131777 7001_ $$0P:(DE-He78)dafca537433ee26708b96d89aba38d29$$aWagner, Lena$$b10
000131777 7001_ $$0P:(DE-He78)022daadde115569e96596dfcd21190a3$$aRabe, Sophie$$b11
000131777 7001_ $$aGhidelli-Disse, Sonja$$b12
000131777 7001_ $$aBantscheff, Marcus$$b13
000131777 7001_ $$aOleś, Andrzej K$$b14
000131777 7001_ $$0P:(DE-HGF)0$$aSłabicki, Mikołaj$$b15
000131777 7001_ $$aMock, Andreas$$b16
000131777 7001_ $$aOakes, Christopher C$$b17
000131777 7001_ $$aWang, Shihui$$b18
000131777 7001_ $$0P:(DE-He78)55dfd5b374ab9bccdb49e06e91345571$$aOppermann, Sina$$b19
000131777 7001_ $$0P:(DE-He78)1d028378e12ca6bdafa3b8b21bc5a9ea$$aLukas, Marina$$b20
000131777 7001_ $$aKim, Vladislav$$b21
000131777 7001_ $$0P:(DE-He78)45440b44791309bd4b7dbb4f73333f9b$$aSill, Martin$$b22
000131777 7001_ $$0P:(DE-He78)e15dfa1260625c69d6690a197392a994$$aBenner, Axel$$b23
000131777 7001_ $$aJauch, Anna$$b24
000131777 7001_ $$aSutton, Lesley Ann$$b25
000131777 7001_ $$aYoung, Emma$$b26
000131777 7001_ $$aRosenquist, Richard$$b27
000131777 7001_ $$0P:(DE-He78)ca03e7517472097f49f822f5d6b0056f$$aLiu, Xiyang$$b28
000131777 7001_ $$0P:(DE-He78)7f506158c27b5827cd9021cd3dad37c8$$aJethwa, Alexander$$b29
000131777 7001_ $$0P:(DE-He78)1121dc6777ecb3a3e48075bbd16246f2$$aLee, Kwang$$b30
000131777 7001_ $$aLewis, Joe$$b31
000131777 7001_ $$aPutzker, Kerstin$$b32
000131777 7001_ $$aLutz, Christoph$$b33
000131777 7001_ $$aRossi, Davide$$b34
000131777 7001_ $$aMokhir, Andriy$$b35
000131777 7001_ $$0P:(DE-He78)6fe098b268bbad1a939e14ed018b295f$$aOellerich, Thomas$$b36
000131777 7001_ $$aZirlik, Katja$$b37
000131777 7001_ $$aHerling, Marco$$b38
000131777 7001_ $$aNguyen-Khac, Florence$$b39
000131777 7001_ $$0P:(DE-He78)4301875630bc997edf491c694ae1f8a9$$aPlass, Christoph$$b40
000131777 7001_ $$aAndersson, Emma$$b41
000131777 7001_ $$aMustjoki, Satu$$b42
000131777 7001_ $$0P:(DE-He78)5bacb661d5d7c0220d8f996d980ad8de$$avon Kalle, Christof$$b43
000131777 7001_ $$aHo, Anthony D$$b44
000131777 7001_ $$aHensel, Manfred$$b45
000131777 7001_ $$aDürig, Jan$$b46
000131777 7001_ $$aRingshausen, Ingo$$b47
000131777 7001_ $$0P:(DE-He78)1beba8f953e7ae7e96e8d3e9a48f10f7$$aZapatka, Marc$$b48
000131777 7001_ $$0P:(DE-HGF)0$$aHuber, Wolfgang$$b49
000131777 7001_ $$0P:(DE-He78)f3d5f16b49eb47520def635be98d5576$$aZenz, Thorsten$$b50
000131777 773__ $$0PERI:(DE-600)2018375-6$$a10.1172/JCI93801$$gVol. 128, no. 1, p. 427 - 445$$n1$$p427 - 445$$tThe @journal of clinical investigation$$v128$$x1558-8238$$y2018
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