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We analyzed the anti-tumor mechanism of tirabrutinib using phosphoproteomic and transcriptomic methods. It is important to check the drug\u2019s selectivity against off-target proteins to understand the anti-tumor mechanism based on the on-target drug effect. Tirabrutinib\u2019s selectivity was evaluated by biochemical kinase profiling assays, peripheral blood mononuclear cell stimulation assays, and the BioMAP system. Next, <jats:italic>in vitro<\/jats:italic> and <jats:italic>in vivo<\/jats:italic> analyses of the anti-tumor mechanisms were conducted in activated B-cell-like diffuse large B-cell lymphoma (ABC-DLBCL) cells followed by phosphoproteomic and transcriptomic analyses. <jats:italic>In vitro<\/jats:italic> kinase assays showed that, compared with ibrutinib, tirabrutinib and other second-generation BTK inhibitors demonstrated a highly selective kinase profile. Data from <jats:italic>in vitro<\/jats:italic> cellular systems showed that tirabrutinib selectively affected B-cells. Tirabrutinib inhibited the cell growth of both TMD8 and U-2932 cells in correlation with the inhibition of BTK autophosphorylation. Phosphoproteomic analysis revealed the downregulation of ERK and AKT pathways in TMD8. In the TMD8 subcutaneous xenograft model, tirabrutinib showed a dose-dependent anti-tumor effect. Transcriptomic analysis indicated that IRF4 gene expression signatures had decreased in the tirabrutinib groups. In conclusion, tirabrutinib exerted an anti-tumor effect by regulating multiple BTK downstream signaling proteins, such as NF-\u03baB, AKT, and ERK, in ABC-DLBCL.<\/jats:p>","DOI":"10.1371\/journal.pone.0282166","type":"journal-article","created":{"date-parts":[[2023,3,10]],"date-time":"2023-03-10T18:35:09Z","timestamp":1678473309000},"page":"e0282166","update-policy":"https:\/\/doi.org\/10.1371\/journal.pone.corrections_policy","source":"Crossref","is-referenced-by-count":15,"title":["Investigation of the anti-tumor mechanism of tirabrutinib, a highly selective Bruton\u2019s tyrosine kinase inhibitor, by phosphoproteomics and transcriptomics"],"prefix":"10.1371","volume":"18","author":[{"ORCID":"https:\/\/orcid.org\/0000-0002-3562-9920","authenticated-orcid":true,"given":"Ryohei","family":"Kozaki","sequence":"first","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Tomoko","family":"Yasuhiro","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-1802-9357","authenticated-orcid":true,"given":"Hikaru","family":"Kato","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-1322-0796","authenticated-orcid":true,"given":"Jun","family":"Murai","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Shingo","family":"Hotta","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Yuko","family":"Ariza","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Shunsuke","family":"Sakai","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Ryu","family":"Fujikawa","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Takao","family":"Yoshida","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"340","published-online":{"date-parts":[[2023,3,10]]},"reference":[{"key":"pone.0282166.ref001","doi-asserted-by":"crossref","first-page":"923","DOI":"10.2147\/JEP.S265284","article-title":"The role of BTK inhibition in the treatment of chronic lymphocytic leukemia: A clinical view","volume":"13","author":"FP Tambaro","year":"2021","journal-title":"J Exp Pharmacol"},{"key":"pone.0282166.ref002","doi-asserted-by":"crossref","first-page":"41","DOI":"10.1016\/j.ctrv.2018.01.002","article-title":"Targeting the B-cell receptor pathway in diffuse large B-cell lymphoma","volume":"65","author":"K Dunleavy","year":"2018","journal-title":"Cancer Treat Rev"},{"key":"pone.0282166.ref003","doi-asserted-by":"crossref","first-page":"25332","DOI":"10.18632\/oncotarget.25011","article-title":"The B cell receptor signaling pathway in mantle cell lymphoma","volume":"9","author":"MI Merolle","year":"2018","journal-title":"Oncotarget"},{"key":"pone.0282166.ref004","doi-asserted-by":"crossref","first-page":"513","DOI":"10.1080\/13543784.2018.1482273","article-title":"Targeting the B cell receptor pathway in non-Hodgkin lymphoma","volume":"27","author":"K Valla","year":"2018","journal-title":"Expert Opin Investig Drugs"},{"key":"pone.0282166.ref005","doi-asserted-by":"crossref","first-page":"722","DOI":"10.1111\/imm.13416","article-title":"The role of Bruton\u2019s tyrosine kinase in the immune system and disease","volume":"164","author":"C McDonald","year":"2021","journal-title":"Immunology"},{"key":"pone.0282166.ref006","doi-asserted-by":"crossref","first-page":"687458","DOI":"10.3389\/fimmu.2021.687458","article-title":"Targeting Bruton\u2019s tyrosine kinase in CLL.","volume":"12","author":"IE Ahn","year":"2021","journal-title":"Front Immunol"},{"key":"pone.0282166.ref007","doi-asserted-by":"crossref","first-page":"909","DOI":"10.1080\/13543784.2017.1349097","article-title":"Bruton\u2019s tyrosine kinase inhibitors in B-cell lymphoma: current experience and future perspectives.","volume":"26","author":"T Seiler","year":"2017","journal-title":"Expert Opin Investig Drugs"},{"key":"pone.0282166.ref008","doi-asserted-by":"crossref","first-page":"263","DOI":"10.1007\/s40265-014-0178-8","article-title":"Ibrutinib: First global approval.","volume":"74","author":"F Cameron","year":"2014","journal-title":"Drugs"},{"key":"pone.0282166.ref009","unstructured":"IMBRUVICA Highlights of Prescribing Information. 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Hershkovitz-Rokah","year":"2018","journal-title":"Br J Haematol"},{"key":"pone.0282166.ref013","doi-asserted-by":"crossref","first-page":"240","DOI":"10.1124\/jpet.117.242909","article-title":"Acalabrutinib (ACP-196): A covalent Bruton tyrosine kinase inhibitor with a differentiated selectivity and in vivo potency profile.","volume":"363","author":"T Barf","year":"2017","journal-title":"J Pharmacol Exp Ther"},{"key":"pone.0282166.ref014","doi-asserted-by":"crossref","first-page":"7923","DOI":"10.1021\/acs.jmedchem.9b00687","article-title":"Discovery of zanubrutinib (BGB-3111), a novel, potent, and selective covalent inhibitor of Bruton\u2019s tyrosine kinase.","volume":"62","author":"Y Guo","year":"2019","journal-title":"J Med Chem"},{"key":"pone.0282166.ref015","doi-asserted-by":"crossref","first-page":"SP226","DOI":"10.37765\/ajmc.2020.88475","article-title":"Second-generation BTK inhibitors hit the treatment bullseye with fewer off-target effects.","volume":"26","author":"ML Shaw","year":"2020","journal-title":"Am J Manag Care."},{"key":"pone.0282166.ref016","doi-asserted-by":"crossref","first-page":"2364","DOI":"10.3324\/haematol.2020.272500","article-title":"Phase II study of acalabrutinib in ibrutinib-intolerant patients with relapsed\/refractory chronic lymphocytic leukemia","volume":"106","author":"KA Rogers","year":"2021","journal-title":"Haematologica"},{"key":"pone.0282166.ref017","doi-asserted-by":"crossref","first-page":"3441","DOI":"10.1200\/JCO.21.01210","article-title":"Acalabrutinib versus ibrutinib in previously treated chronic lymphocytic leukemia: Results of the first randomized phase III trial","volume":"39","author":"JC Byrd","year":"2021","journal-title":"J Clin Oncol"},{"key":"pone.0282166.ref018","article-title":"First interim analysis of ALPINE study: Results of a phase 3 randomized study of zanubrutinib vs ibrutinib in patients with relapsed\/refractory chronic lymphocytic leukemia\/small lymphocytic lymphoma","author":"P Hillmen","year":"2021","journal-title":"Presented at"},{"key":"pone.0282166.ref019","doi-asserted-by":"crossref","first-page":"277","DOI":"10.1358\/dot.2021.57.4.3264113","article-title":"Tirabrutinib hydrochloride for B-cell lymphomas.","volume":"57","author":"W Munakata","year":"2021","journal-title":"Drugs Today (Barc)."},{"key":"pone.0282166.ref020","doi-asserted-by":"crossref","first-page":"88","DOI":"10.1038\/nature08638","article-title":"Chronic active B-cell-receptor signalling in diffuse large B-cell lymphoma","volume":"463","author":"RE Davis","year":"2010","journal-title":"Nature"},{"key":"pone.0282166.ref021","doi-asserted-by":"crossref","first-page":"595","DOI":"10.1111\/bjh.16118","article-title":"Single and combined BTK and PI3K\u03b4 inhibition with acalabrutinib and ACP-319 in pre-clinical models of aggressive lymphomas","volume":"187","author":"F Spriano","year":"2019","journal-title":"Br J Haematol"},{"key":"pone.0282166.ref022","doi-asserted-by":"crossref","first-page":"909","DOI":"10.1111\/cas.12682","article-title":"Comprehensive transcriptomic analysis of molecularly targeted drugs in cancer for target pathway evaluation","volume":"106","author":"T Mashima","year":"2015","journal-title":"Cancer Sci"},{"key":"pone.0282166.ref023","doi-asserted-by":"crossref","first-page":"1111","DOI":"10.1016\/j.ejca.2010.01.005","article-title":"Inhibition profiles of phosphatidylinositol 3-kinase inhibitors against PI3K superfamily and human cancer cell line panel JFCR39","volume":"46","author":"D Kong","year":"2010","journal-title":"Eur J Cancer"},{"key":"pone.0282166.ref024","doi-asserted-by":"crossref","first-page":"1385","DOI":"10.1016\/j.leukres.2006.05.003","article-title":"Establishment of a novel B-cell lymphoma cell line with suppressed growth by gamma-secretase inhibitors","volume":"30","author":"S Tohda","year":"2006","journal-title":"Leuk Res"},{"key":"pone.0282166.ref025","doi-asserted-by":"crossref","first-page":"2179","DOI":"10.1080\/1042819021000032917","article-title":"A novel B-cell line (U-2932) established from a patient with diffuse large B-cell lymphoma following Hodgkin lymphoma.","volume":"43","author":"RM Amini","year":"2002","journal-title":"Leuk Lymphoma"},{"key":"pone.0282166.ref026","doi-asserted-by":"crossref","first-page":"127","DOI":"10.1038\/nbt1358","article-title":"A quantitative analysis of kinase inhibitor selectivity","volume":"26","author":"MW Karaman","year":"2008","journal-title":"Nat Biotechnol"},{"key":"pone.0282166.ref027","doi-asserted-by":"crossref","first-page":"110","DOI":"10.1111\/gtc.12022","article-title":"Activity-based kinase profiling of approved tyrosine kinase inhibitors","volume":"18","author":"D Kitagawa","year":"2013","journal-title":"Genes Cells"},{"key":"pone.0282166.ref028","unstructured":"Thermo Fisher Scientific. 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(Basel)."},{"key":"pone.0282166.ref032","doi-asserted-by":"crossref","first-page":"1343","DOI":"10.1016\/j.jprot.2011.11.004","article-title":"Dual phosphoproteomics and chemical proteomics analysis of erlotinib and gefitinib interference in acute myeloid leukemia cells","volume":"75","author":"C Weber","year":"2012","journal-title":"J Proteomics"},{"key":"pone.0282166.ref033","doi-asserted-by":"crossref","first-page":"635","DOI":"10.1016\/j.cell.2006.09.026","article-title":"Global, in vivo, and site-specific phosphorylation dynamics in signaling networks.","volume":"127","author":"JV Olsen","year":"2006","journal-title":"Cell"},{"key":"pone.0282166.ref034","doi-asserted-by":"crossref","first-page":"15545","DOI":"10.1073\/pnas.0506580102","article-title":"Gene set enrichment analysis: a knowledge-based approach for interpreting genome-wide expression profiles","volume":"102","author":"A Subramanian","year":"2005","journal-title":"Proc Natl Acad Sci U S A"},{"key":"pone.0282166.ref035","doi-asserted-by":"crossref","first-page":"417","DOI":"10.1016\/j.cels.2015.12.004","article-title":"The Molecular Signatures Database (MSigDB) hallmark gene set collection.","volume":"1","author":"A Liberzon","year":"2015","journal-title":"Cell Syst"},{"key":"pone.0282166.ref036","doi-asserted-by":"crossref","first-page":"1739","DOI":"10.1093\/bioinformatics\/btr260","article-title":"Molecular signatures database (MSigDB) 3.0.","volume":"27","author":"A Liberzon","year":"2011","journal-title":"Bioinformatics"},{"key":"pone.0282166.ref037","doi-asserted-by":"crossref","first-page":"2443","DOI":"10.1161\/CIRCULATIONAHA.120.049210","article-title":"Ibrutinib-mediated atrial fibrillation attributable to inhibition of C-terminal Src kinase","volume":"142","author":"L Xiao","year":"2020","journal-title":"Circulation"},{"key":"pone.0282166.ref038","doi-asserted-by":"crossref","first-page":"257","DOI":"10.1038\/nri2745","article-title":"Regulation of immune cell development through soluble inositol-1,3,4,5-tetrakisphosphate","volume":"10","author":"K Sauer","year":"2010","journal-title":"Nat Rev Immunol"},{"key":"pone.0282166.ref039","doi-asserted-by":"crossref","first-page":"15192","DOI":"10.1074\/jbc.M009130200","article-title":"Regulation of membrane targeting of the G protein-coupled receptor kinase 2 by protein kinase A and its anchoring protein AKAP79","volume":"276","author":"M Cong","year":"2001","journal-title":"J Biol Chem"},{"key":"pone.0282166.ref040","doi-asserted-by":"crossref","first-page":"112","DOI":"10.3389\/fphar.2019.00112","article-title":"G protein-coupled receptor kinase 2 (GRK2) as a potential therapeutic target in cardiovascular and metabolic diseases.","volume":"10","author":"C Murga","year":"2019","journal-title":"Front Pharmacol."},{"key":"pone.0282166.ref041","doi-asserted-by":"crossref","first-page":"215","DOI":"10.1016\/j.molcel.2004.11.055","article-title":"Regulation of Raf-1 by direct feedback phosphorylation","volume":"17","author":"MK Dougherty","year":"2005","journal-title":"Mol Cell"},{"key":"pone.0282166.ref042","doi-asserted-by":"crossref","first-page":"4619","DOI":"10.1038\/sj.emboj.7601891","article-title":"Phosphorylation at Ser244 by CK1 determines nuclear localization and substrate targeting of PKD2","volume":"26","author":"J von Blume","year":"2007","journal-title":"EMBO J"},{"key":"pone.0282166.ref043","doi-asserted-by":"crossref","first-page":"23773","DOI":"10.1074\/jbc.M300226200","article-title":"Protein kinase C nu\/protein kinase D3 nuclear localization, catalytic activation, and intracellular redistribution in response to G protein-coupled receptor agonists","volume":"278","author":"O Rey","year":"2003","journal-title":"J Biol Chem"},{"key":"pone.0282166.ref044","doi-asserted-by":"crossref","first-page":"1785","DOI":"10.1002\/j.1460-2075.1995.tb07167.x","article-title":"ATF-2 contains a phosphorylation-dependent transcriptional activation domain","volume":"14","author":"C Livingstone","year":"1995","journal-title":"EMBO J"},{"key":"pone.0282166.ref045","doi-asserted-by":"crossref","first-page":"3782","DOI":"10.1093\/emboj\/cdf361","article-title":"Growth factors can activate ATF2 via a two-step mechanism: phosphorylation of Thr71 through the Ras-MEK-ERK pathway and of Thr69 through RalGDS-Src-p38","volume":"21","author":"DM Ouwens","year":"2002","journal-title":"EMBO J"},{"key":"pone.0282166.ref046","doi-asserted-by":"crossref","first-page":"951","DOI":"10.1002\/j.1460-2075.1995.tb07076.x","article-title":"ERK phosphorylation potentiates Elk-1-mediated ternary complex formation and transactivation","volume":"14","author":"H Gille","year":"1995","journal-title":"EMBO J"},{"key":"pone.0282166.ref047","doi-asserted-by":"crossref","first-page":"e2478","DOI":"10.1371\/journal.pone.0002478","article-title":"B-MYB is essential for normal cell cycle progression and chromosomal stability of embryonic stem cells","volume":"3","author":"KV Tarasov","year":"2008","journal-title":"PLoS One"},{"key":"pone.0282166.ref048","doi-asserted-by":"crossref","first-page":"22","DOI":"10.3390\/cells5020022","article-title":"Post-translational modifications of RelB NF-\u03baB subunit and associated functions.","volume":"5","author":"V Baud","year":"2016","journal-title":"Cells"},{"key":"pone.0282166.ref049","doi-asserted-by":"crossref","first-page":"205","DOI":"10.3390\/ijms18010205","article-title":"Post-translational modifications of the TAK1-TAB complex.","volume":"18","author":"Y Hirata","year":"2017","journal-title":"Int J Mol Sci"},{"key":"pone.0282166.ref050","doi-asserted-by":"crossref","first-page":"817","DOI":"10.1016\/S1074-7613(00)00079-0","article-title":"BCAP: the tyrosine kinase substrate that connects B cell receptor to phosphoinositide 3-kinase activation","volume":"13","author":"T Okada","year":"2000","journal-title":"Immunity"},{"key":"pone.0282166.ref051","doi-asserted-by":"crossref","first-page":"4511","DOI":"10.1128\/MCB.23.13.4511-4521.2003","article-title":"Protein kinase B\/Akt binds and phosphorylates PED\/PEA-15, stabilizing its antiapoptotic action","volume":"23","author":"A Trencia","year":"2003","journal-title":"Mol Cell Biol"},{"key":"pone.0282166.ref052","doi-asserted-by":"crossref","first-page":"27828","DOI":"10.1074\/jbc.M303417200","article-title":"Heat shock protein 27 controls apoptosis by regulating Akt activation","volume":"278","author":"MJ Rane","year":"2003","journal-title":"J Biol Chem"},{"key":"pone.0282166.ref053","doi-asserted-by":"crossref","first-page":"4281","DOI":"10.1038\/sj.onc.1208590","article-title":"Akt phosphorylates the Y-box binding protein 1 at Ser102 located in the cold shock domain and affects the anchorage-independent growth of breast cancer cells","volume":"24","author":"BW Sutherland","year":"2005","journal-title":"Oncogene"},{"key":"pone.0282166.ref054","doi-asserted-by":"crossref","first-page":"1487","DOI":"10.1038\/onc.2014.91","article-title":"Nuclear PRAS40 couples the Akt\/mTORC1 signaling axis to the RPL11-HDM2-p53 nucleolar stress response pathway","volume":"34","author":"JJ Havel","year":"2015","journal-title":"Oncogene"},{"key":"pone.0282166.ref055","doi-asserted-by":"crossref","first-page":"20206","DOI":"10.1074\/jbc.274.29.20206","article-title":"p90(RSK) is a serum-stimulated Na+\/H+ exchanger isoform-1 kinase. Regulatory phosphorylation of serine 703 of Na+\/H+ exchanger isoform-1.","volume":"274","author":"E Takahashi","year":"1999","journal-title":"J Biol Chem"},{"key":"pone.0282166.ref056","doi-asserted-by":"crossref","first-page":"881","DOI":"10.1161\/CIRCRESAHA.108.175877","article-title":"Protein kinase B\/Akt phosphorylates and inhibits the cardiac Na+\/H+ exchanger NHE1","volume":"103","author":"AK Snabaitis","year":"2008","journal-title":"Circ Res"},{"key":"pone.0282166.ref057","doi-asserted-by":"crossref","first-page":"9986","DOI":"10.1128\/MCB.24.22.9986-9999.2004","article-title":"Mechanism of B-cell receptor-induced phosphorylation and activation of phospholipase C-gamma2","volume":"24","author":"YJ Kim","year":"2004","journal-title":"Mol Cell Biol"},{"key":"pone.0282166.ref058","doi-asserted-by":"crossref","first-page":"2619","DOI":"10.1042\/BCJ20210139","article-title":"Inhibitory feedback control of NF-\u03baB signalling in health and disease","volume":"478","author":"JA Prescott","year":"2021","journal-title":"Biochem J"},{"key":"pone.0282166.ref059","doi-asserted-by":"crossref","first-page":"e10269","DOI":"10.7717\/peerj.10269","article-title":"Identification of hub genes associated with the pathogenesis of diffuse large B-cell lymphoma subtype one characterized by host response via integrated bioinformatic analyses.","volume":"8","author":"L Zhou","year":"2020","journal-title":"PeerJ"},{"key":"pone.0282166.ref060","doi-asserted-by":"crossref","first-page":"871","DOI":"10.1182\/blood.2020009404","article-title":"Dimethyl fumarate induces ferroptosis and impairs NF-\u03baB\/STAT3 signaling in DLBCL.","volume":"138","author":"A Schmitt","year":"2021","journal-title":"Blood"},{"key":"pone.0282166.ref061","doi-asserted-by":"crossref","first-page":"129531","DOI":"10.1016\/j.bbagen.2020.129531","article-title":"Biochemical characterization of tirabrutinib and other irreversible inhibitors of Bruton\u2019s tyrosine kinase reveals differences in on\u2014and off\u2014target inhibition","volume":"1864","author":"A Liclican","year":"2020","journal-title":"Biochim Biophys Acta Gen Subj"},{"key":"pone.0282166.ref062","doi-asserted-by":"crossref","first-page":"922","DOI":"10.1038\/nm.3884","article-title":"Targeting B cell receptor signaling with ibrutinib in diffuse large B cell lymphoma","volume":"21","author":"WH Wilson","year":"2015","journal-title":"Nat Med"},{"key":"pone.0282166.ref063","doi-asserted-by":"crossref","first-page":"1297","DOI":"10.1084\/jem.188.7.1297","article-title":"Different protein tyrosine kinases are required for B cell antigen receptor-mediated activation of extracellular signal-regulated kinase, c-Jun NH2-terminal kinase 1, and p38 mitogen-activated protein kinase","volume":"188","author":"A Jiang","year":"1998","journal-title":"J Exp Med"},{"key":"pone.0282166.ref064","doi-asserted-by":"crossref","first-page":"649","DOI":"10.1038\/leu.2013.358","article-title":"BTK inhibition targets in vivo CLL proliferation through its effects on B-cell receptor signaling activity","volume":"28","author":"S Cheng","year":"2014","journal-title":"Leukemia"},{"key":"pone.0282166.ref065","doi-asserted-by":"crossref","first-page":"29860","DOI":"10.18632\/oncotarget.5007","article-title":"ELK1 is up-regulated by androgen in bladder cancer cells and promotes tumor progression","volume":"6","author":"T Kawahara","year":"2015","journal-title":"Oncotarget"},{"key":"pone.0282166.ref066","doi-asserted-by":"crossref","first-page":"1780","DOI":"10.1182\/blood-2015-07-655647","article-title":"CARMA1- and MyD88-dependent activation of Jun\/ATF-type AP-1 complexes is a hallmark of ABC diffuse large B-cell lymphomas","volume":"127","author":"M Juilland","year":"2016","journal-title":"Blood"},{"key":"pone.0282166.ref067","doi-asserted-by":"crossref","first-page":"157","DOI":"10.1016\/j.yexcr.2016.07.003","article-title":"Y-box-binding protein-1 (YB-1) promotes cell proliferation, adhesion and drug resistance in diffuse large B-cell lymphoma.","volume":"346","author":"X Miao","year":"2016","journal-title":"Exp Cell Res"},{"key":"pone.0282166.ref068","doi-asserted-by":"crossref","first-page":"15619","DOI":"10.1074\/jbc.M800723200","article-title":"Regulation of proline-rich Akt substrate of 40 kDa (PRAS40) function by mammalian target of rapamycin complex 1 (mTORC1)-mediated phosphorylation.","volume":"283","author":"L Wang","year":"2008","journal-title":"J Biol Chem"},{"key":"pone.0282166.ref069","doi-asserted-by":"crossref","first-page":"64","DOI":"10.1016\/j.ccell.2016.12.003","article-title":"Simultaneous inhibition of PI3K\u03b4 and PI3K\u03b1 induces ABC-DLBCL regression by blocking BCR-dependent and -independent activation of NF-\u03baB and AKT","volume":"31","author":"J Paul","year":"2017","journal-title":"Cancer Cell"},{"key":"pone.0282166.ref070","doi-asserted-by":"crossref","first-page":"9086","DOI":"10.1074\/jbc.M211295200","article-title":"Regulation of protein kinase Cnu by the B-cell antigen receptor","volume":"278","author":"SA Matthews","year":"2003","journal-title":"J Biol Chem"},{"key":"pone.0282166.ref071","doi-asserted-by":"crossref","first-page":"73","DOI":"10.1111\/j.1600-065X.2012.01113.x","article-title":"The diverse roles of IRF4 in late germinal center B-cell differentiation","volume":"247","author":"NS De Silva","year":"2012","journal-title":"Immunol Rev"},{"key":"pone.0282166.ref072","doi-asserted-by":"crossref","first-page":"5058","DOI":"10.1002\/cncr.26135","article-title":"Higher response to lenalidomide in relapsed\/refractory diffuse large B-cell lymphoma in nongerminal center B-cell-like than in germinal center B-cell-like phenotype","volume":"117","author":"FJ Hernandez-Ilizaliturri","year":"2011","journal-title":"Cancer"},{"key":"pone.0282166.ref073","doi-asserted-by":"crossref","first-page":"723","DOI":"10.1016\/j.ccr.2012.05.024","article-title":"Exploiting synthetic lethality for the therapy of ABC diffuse large B cell lymphoma","volume":"21","author":"Y Yang","year":"2012","journal-title":"Cancer Cell"},{"key":"pone.0282166.ref074","doi-asserted-by":"crossref","first-page":"325","DOI":"10.1111\/j.1365-2141.2011.08689.x","article-title":"Lenalidomide downregulates the cell survival factor, interferon regulatory factor-4, providing a potential mechanistic link for predicting response","volume":"154","author":"A Lopez-Girona","year":"2011","journal-title":"Br J Haematol"},{"key":"pone.0282166.ref075","doi-asserted-by":"crossref","first-page":"1797","DOI":"10.1038\/onc.2015.245","article-title":"Immunomodulatory drugs target IKZF1-IRF4-MYC axis in primary effusion lymphoma in a cereblon-dependent manner and display synergistic cytotoxicity with BRD4 inhibitors","volume":"35","author":"R Gopalakrishnan","year":"2016","journal-title":"Oncogene"},{"key":"pone.0282166.ref076","doi-asserted-by":"crossref","first-page":"2422","DOI":"10.1038\/s41379-020-0616-y","article-title":"Evolving insights into the genomic complexity and immune landscape of diffuse large B-cell lymphoma: opportunities for novel biomarkers.","volume":"33","author":"S El Hussein","year":"2020","journal-title":"Mod Pathol"},{"key":"pone.0282166.ref077","doi-asserted-by":"crossref","first-page":"1396","DOI":"10.1056\/NEJMoa1801445","article-title":"Genetics and pathogenesis of diffuse large B-cell lymphoma","volume":"378","author":"R Schmitz","year":"2018","journal-title":"N Engl J Med"},{"key":"pone.0282166.ref078","doi-asserted-by":"crossref","first-page":"1643","DOI":"10.1016\/j.ccell.2021.10.006","article-title":"Effect of ibrutinib with R-CHOP chemotherapy in genetic subtypes of DLBCL","volume":"39","author":"WH Wilson","year":"2021","journal-title":"Cancer Cell"},{"key":"pone.0282166.ref079","doi-asserted-by":"crossref","first-page":"3579","DOI":"10.4161\/cc.26822","article-title":"mTOR\/PRAS40 interaction: hypertrophy or proliferation","volume":"12","author":"M V\u00f6lkers","year":"2013","journal-title":"Cell 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