@article {burger2016clonal,
	title = {Clonal evolution in patients with chronic lymphocytic leukaemia developing resistance to BTK inhibition},
	journal = {Nature communications},
	volume = {7},
	year = {2016},
	pages = {11589},
	publisher = {Nature Publishing Group},
	abstract = {
	
		Resistance to the Bruton{\textquoteright}s tyrosine kinase (BTK) inhibitor ibrutinib has been attributed solely to mutations in\&nbsp;BTK\&nbsp;and related pathway molecules. 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\&nbsp;BTK-C481S\&nbsp;mutation or multiple\&nbsp;PLCG2\&nbsp;mutations. The other three patients exhibit an expansion of clones harbouring\&nbsp;del(8p) with additional driver mutations (EP300, MLL2\&nbsp;and\&nbsp;EIF2A), with one patient developing\&nbsp;trans-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\&nbsp;del(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.
	

},
	url = {https://www.nature.com/articles/ncomms11589},
	author = {Burger, Jan A and Landau, Dan A and Taylor-Weiner, Amaro and Bozic, Ivana and Zhang, Huidan and Sarosiek, Kristopher and Wang, Lili and Stewart, Chip and Fan, Jean and Hoellenriegel, Julia and others}
}
