Dataset Information

Clonal evolution in patients with chronic lymphocytic leukaemia developing resistance to BTK inhibition.

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.

SUBMITTER: Burger JA

PROVIDER: S-EPMC4876453 | biostudies-literature | 2016 May

REPOSITORIES: biostudies-literature

ACCESS DATA

Publications

Clonal evolution in patients with chronic lymphocytic leukaemia developing resistance to BTK inhibition.

Burger Jan A JA Landau Dan A DA Taylor-Weiner Amaro A Bozic Ivana I Zhang Huidan H Sarosiek Kristopher K Wang Lili L Stewart Chip C Fan Jean J Hoellenriegel Julia J Sivina Mariela M Dubuc Adrian M AM Fraser Cameron C Han Yulong Y Li Shuqiang S Livak Kenneth J KJ Zou Lihua L Wan Youzhong Y Konoplev Sergej S Sougnez Carrie C Brown Jennifer R JR Abruzzo Lynne V LV Carter Scott L SL Keating Michael J MJ Davids Matthew S MS Wierda William G WG Cibulskis Kristian K Zenz Thorsten T Werner Lillian L Dal Cin Paola P Kharchencko Peter P Neuberg Donna D Kantarjian Hagop H Lander Eric E Gabriel Stacey S O'Brien Susan S Letai Anthony A Weitz David A DA Nowak Martin A MA Getz Gad G Wu Catherine J CJ

Nature communications 20160520

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, M ...[more]

PMID: 27199251

Similar Datasets

Project description:Genetic and epigenetic intra-tumoral heterogeneity cooperate to shape the evolutionary course of cancer1. Chronic lymphocytic leukaemia (CLL) is a highly informative model for cancer evolution as it undergoes substantial genetic diversification and evolution after therapy2,3. The CLL epigenome is also an important disease-defining feature4,5, and growing populations of cells in CLL diversify by stochastic changes in DNA methylation known as epimutations6. However, previous studies using bulk sequencing methods to analyse the patterns of DNA methylation were unable to determine whether epimutations affect CLL populations homogeneously. Here, to measure the epimutation rate at single-cell resolution, we applied multiplexed single-cell reduced-representation bisulfite sequencing to B cells from healthy donors and patients with CLL. We observed that the common clonal origin of CLL results in a consistently increased epimutation rate, with low variability in the cell-to-cell epimutation rate. By contrast, variable epimutation rates across healthy B cells reflect diverse evolutionary ages across the trajectory of B cell differentiation, consistent with epimutations serving as a molecular clock. Heritable epimutation information allowed us to reconstruct lineages at high-resolution with single-cell data, and to apply this directly to patient samples. The CLL lineage tree shape revealed earlier branching and longer branch lengths than in normal B cells, reflecting rapid drift after the initial malignant transformation and a greater proliferative history. Integration of single-cell bisulfite sequencing analysis with single-cell transcriptomes and genotyping confirmed that genetic subclones mapped to distinct clades, as inferred solely on the basis of epimutation information. Finally, to examine potential lineage biases during therapy, we profiled serial samples during ibrutinib-associated lymphocytosis, and identified clades of cells that were preferentially expelled from the lymph node after treatment, marked by distinct transcriptional profiles. The single-cell integration of genetic, epigenetic and transcriptional information thus charts the lineage history of CLL and its evolution with therapy.

Dataset Information

Clonal evolution in patients with chronic lymphocytic leukaemia developing resistance to BTK inhibition.

Publications

Clonal evolution in patients with chronic lymphocytic leukaemia developing resistance to BTK inhibition.

Similar Datasets

OmicsDI is part of the ELIXIR infrastructure

Tweets