{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2025,10,30]],"date-time":"2025-10-30T22:31:39Z","timestamp":1761863499564},"reference-count":39,"publisher":"Wiley","issue":"1","license":[{"start":{"date-parts":[[2015,9,10]],"date-time":"2015-09-10T00:00:00Z","timestamp":1441843200000},"content-version":"vor","delay-in-days":0,"URL":"http:\/\/onlinelibrary.wiley.com\/termsAndConditions#vor"}],"funder":[{"DOI":"10.13039\/501100000001","name":"Alberta Cancer Foundation","doi-asserted-by":"publisher","award":["25999"],"award-info":[{"award-number":["25999"]}],"id":[{"id":"10.13039\/501100000001","id-type":"DOI","asserted-by":"publisher"}]}],"content-domain":{"domain":[],"crossmark-restriction":false},"short-container-title":["Hematological Oncology"],"published-print":{"date-parts":[[2017,3]]},"abstract":"<jats:title>Abstract<\/jats:title><jats:p>Mantle cell lymphoma (MCL) is an aggressive disease with frequent relapse. Targeted therapies against B\u2010cell receptor (BCR) molecules have demonstrated improved outcomes in relapsed cases. However, clinical responses are slow and selective, with failure to attain complete remission in a significant subset of patients. Complex interaction of BCR signal transduction with toll\u2010like receptor (TLR) and other pathways in MCL remains unknown, thus averting progress in development of targeted therapies. We have performed detailed digital quantification of BCR\/TLR signalling molecules and their effector pathways in a cohort (<jats:italic>n<\/jats:italic>\u2009=\u200981) of MCL patients and correlated these data with overall survival. Hierarchical clustering model based on BCR\/TLR genes revealed two distinct (BCR<jats:sup>high<\/jats:sup> and BCR<jats:sup>low<\/jats:sup>) subsets of patients (<jats:italic>n<\/jats:italic>\u2009=\u200932; 40%) with significant differences in expression (&gt;1.5\u2010fold change; <jats:italic>p<\/jats:italic>\u2009&lt;\u20090.05). Higher levels of <jats:italic>BTK<\/jats:italic>\/<jats:italic>SYK<\/jats:italic>\/<jats:italic>BLNK<\/jats:italic>\/<jats:italic>CARD11<\/jats:italic>\/<jats:italic>PLCG<\/jats:italic> signalosome and lower expression of <jats:italic>MALT1<\/jats:italic>\/<jats:italic>BCL10<\/jats:italic> genes suggested tonic pattern of BCR activation. Amplified expression of <jats:italic>TLR6<\/jats:italic>\/<jats:italic>TLR7<\/jats:italic>\/<jats:italic>TLR9<\/jats:italic> was noted in concert with hyper\u2010responsiveness of BCR machinery. <jats:italic>MYD88<\/jats:italic>, a key TLR adaptor molecule, was not upregulated in any of these clusters, which may suggest a \u2018cross\u2010talk\u2019 between BCR and TLR pathways. In sync with BCR\/TLR signalling, we recorded significantly enhanced expression of genes associated with NF\u2010kB pathway in BCR<jats:sup>high<\/jats:sup> subset of MCL patients. On univariate analysis, the BCR<jats:sup>high<\/jats:sup> patients showed a trend towards inferior clinical response to a standardized treatment protocol, compared with the BCR<jats:sup>low<\/jats:sup> group (<jats:italic>log rank<\/jats:italic>, <jats:italic>p<\/jats:italic>\u2009=\u20090.043). In conclusion, we have identified hyperactive BCR\/TLR signalling pathways and their effector downstream targets in a subset of MCL patients and associated it with poor clinical outcomes. Our study provides quantitative evidence at RNA expression level of possible concomitant collaboration between TLR and BCR signalling molecules in MCL. These data will provide further insights for future functional studies and, hence, development of targeted therapies for MCL patients. Copyright \u00a9 2015 John Wiley &amp; Sons, Ltd.<\/jats:p>","DOI":"10.1002\/hon.2251","type":"journal-article","created":{"date-parts":[[2015,9,10]],"date-time":"2015-09-10T14:39:22Z","timestamp":1441895962000},"page":"79-86","source":"Crossref","is-referenced-by-count":16,"title":["Concomitant high expression of Toll\u2010like receptor (TLR) and B\u2010cell receptor (BCR) signalling molecules has clinical implications in mantle cell lymphoma"],"prefix":"10.1002","volume":"35","author":[{"given":"Ariz","family":"Akhter","sequence":"first","affiliation":[{"name":"Division of Hematology and Transfusion Medicine, Department of Pathology and Laboratory Medicine University of Calgary\/Calgary Laboratory Services (CLS)  Calgary Alberta Canada"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Lesley","family":"Street","sequence":"additional","affiliation":[{"name":"Division of Hematology and Hematologic Malignancies, Tom Baker Cancer Center University of Calgary  Calgary 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