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Using whole-exome and deep-targeted sequencing, we dissect evolution of ibrutinib resistance in serial samples from five chronic lymphocytic leukaemia patients. In two patients, we detect\n                    <jats:italic>BTK-C481S<\/jats:italic>\n                    mutation or multiple\n                    <jats:italic>PLCG2<\/jats:italic>\n                    mutations. The other three patients exhibit an expansion of clones harbouring\n                    <jats:italic>del<\/jats:italic>\n                    (8p) with additional driver mutations (\n                    <jats:italic>EP300, MLL2<\/jats:italic>\n                    and\n                    <jats:italic>EIF2A<\/jats:italic>\n                    ), with one patient developing\n                    <jats:italic>trans<\/jats:italic>\n                    -differentiation into CD19-negative histiocytic sarcoma. Using droplet-microfluidic technology and growth kinetic analyses, we demonstrate the presence of ibrutinib-resistant subclones and estimate subclone size before treatment initiation. Haploinsufficiency of TRAIL-R, a consequence of\n                    <jats:italic>del<\/jats:italic>\n                    (8p), results in TRAIL insensitivity, which may contribute to ibrutinib resistance. These findings demonstrate that the ibrutinib therapy favours selection and expansion of rare subclones already present before ibrutinib treatment, and provide insight into the heterogeneity of genetic changes associated with ibrutinib resistance.\n                  <\/jats:p>","DOI":"10.1038\/ncomms11589","type":"journal-article","created":{"date-parts":[[2016,5,21]],"date-time":"2016-05-21T05:14:21Z","timestamp":1463807661000},"update-policy":"https:\/\/doi.org\/10.1007\/springer_crossmark_policy","source":"Crossref","is-referenced-by-count":319,"title":["Clonal evolution in patients with chronic lymphocytic leukaemia developing resistance to BTK inhibition"],"prefix":"10.1038","volume":"7","author":[{"given":"Jan A.","family":"Burger","sequence":"first","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Dan 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