Clonal evolution in patients with chronic lymphocytic leukaemia developing resistance to BTK inhibition
Year: 2016
Type: article
Study design: Case Report
Abstract: Resistance to the Bruton's tyrosine kinase (BTK) inhibitor ibrutinib has been attributed solely to mutations in BTK 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 BTK-C481S mutation or multiple PLCG2 mutations. The other three patients exhibit an expansion of clones harbouring del(8p) with additional driver mutations (EP300, MLL2 and EIF2A), with one patient developing 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 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.
Source: Nature Communications
DOI: 10.1038/ncomms11589
Authors: Jan A. Burger, Dan A. Landau, Amaro Taylor-Weiner, Ivana Bozic, Huidan Zhang, Kristopher Sarosiek, Lili Wang, Chip Stewart, Jean Fan, Julia Hoellenriegel, Mariela Sivina, Adrian M. Dubuc, Cameron Fraser, Yulong Han, Shuqiang Li, Kenneth J. Livak, Lihua Zou, Youzhong Wan, Sergej Konoplev, Carrie Sougnez, Jennifer R. Brown, Lynne V. Abruzzo, Scott L. Carter, Michael J. Keating, Matthew S. Davids, William G. Wierda, Kristian Cibulskis, Thorsten Zenz, Lillian Werner, Paola Dal Cin, Peter Kharchencko, Donna Neuberg, Hagop Kantarjian, Eric Lander, Stacey Gabriel, Susan O’Brien, Anthony Letai, David A. Weitz, Martin A. Nowak, Gad Getz, Catherine J. Wu
Institutions: The University of Texas MD Anderson Cancer Center, Broad Institute, New York Genome Center, Weill Cornell Medicine, Harvard University, China Medical University, Dana-Farber Cancer Institute, Brigham and Women's Hospital, Xi'an Jiaotong University, Standard BioTools (United States), German Cancer Research Center
Language: English
Subfield: Genetics
Field: Medicine
Domain: Health Sciences
Open Access status: gold
Estimated APC paid: $6,990
Funders: National Science Foundation, John Templeton Foundation, Harvard University, Deutsches Krebsforschungszentrum, National Natural Science Foundation of China, University of Texas MD Anderson Cancer Center, Stand Up To Cancer, Materials Research Science and Engineering Center, Harvard University, National Heart, Lung, and Blood Institute, National Human Genome Research Institute, National Cancer Institute, Division of Materials Research
Awards: G1020486556, G111615301, G1468253849, G1581977058, G1587441952, G1609525565, G1637850186, G1791404784, G1867270842, G1901027039, G2254063607, G2684269125, G3366412161, G3400514463, G3527015187, G3576276198, G3953734904, Soft Materials: Synthesis and Properties, G4220372196, G4663567540, G5430666879, G5484137802, NNIN: National Nanotechnology Infrastructure Network, 基于超高通量液滴微反应器的单细胞水平肿瘤异质性研究体系的建立, The role of the SF3B1 splicing factor in chronic lymphocytic leukemia, Statistical methods for analysis of single-cell variability, G7201857753, Graduate Research Fellowship Program (GRFP), Materials Research Science and Engineering Center, G8874911805, Comprehensive dissection of the CLL genome & phenome to improve patient outcomes
OpenAlex ID: W2408036343