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- Study Description
We analyzed clonal evolution in serial samples from five CLL patients who became resistant to the Bruton's tyrosine kinase (BTK) inhibitor ibrutinib, using whole-exome and deep targeted sequencing. We observe a BTK-C481S mutation in one of five patients, and multiple PLCG2 mutations in a second patient. The other patients had an expansion of clones harboring del(8p) carrying additional driver mutations (EP300, MLL2, EIF2A), with one patient developing trans-differentiation into CD19-negative histiocytic sarcoma. We calculated the growth kinetics of ibrutinib-resistant subclones and estimated the size of the resistant clones at treatment initiation, which we validated by droplet-microfluidic technology. Haplo-insufficiency of TRAIL-R, a consequence of del(8p), led to TRAIL insensitivity which may contribute to development of ibrutinib resistance. These findings demonstrate that ibrutinib therapy has the potential to lead to clonal selection and expansion of rare cell populations already present at the time of treatment initiation. They also provide insight into the heterogeneity of genetic changes associated with ibrutinib resistance, previously attributed solely to mutations in BTK and related pathway molecules.
- Study Design:
- Prospective Longitudinal Cohort
- Study Type:
- Total number of consented subjects: 5
- Subject Sample Telemetry Report (SSTR)
- Study Design:
- Authorized Access
- Publicly Available Data (Public ftp)
- Molecular Data
Type Source Platform Number of Oligos/SNPs SNP Batch Id Comment Whole Exome Sequencing Agilent SureSelect Custom Whole Exome Library Construction N/A N/A RNA Sequencing Illumina TruSeq N/A N/A
- Selected Publications
- Diseases/Traits Related to Study (MeSH terms)
- Primary Phenotype: Leukemia, Lymphocytic, Chronic, B-Cell
- Links to Related Genes
- Links to Related Resources
- Authorized Data Access Requests
- Study Attribution
- Catherine Wu, MD. Dana Farber Cancer Institute, Boston, MA, USA.
- Institute. Broad Institute, Cambridge, MA, USA.
- U54 HG003067. National Human Genome Research Institute, National Institutes of Health, Bethesda, MD, USA.
- Principal Investigator