Abstract
The Bruton tyrosine kinase (BTK) inhibitor ibrutinib provides effective treatment for patients with chronic lymphocytic leukemia (CLL), despite extensive heterogeneity in this disease. To define the underlining regulatory dynamics, we analyze high-resolution time courses of ibrutinib treatment in patients with CLL, combining immune-phenotyping, single-cell transcriptome profiling, and chromatin mapping. We identify a consistent regulatory program starting with a sharp decrease of NF-κB binding in CLL cells, which is followed by reduced activity of lineage-defining transcription factors, erosion of CLL cell identity, and acquisition of a quiescence-like gene signature. We observe patient-to-patient variation in the speed of execution of this program, which we exploit to predict patient-specific dynamics in the response to ibrutinib based on the pre-treatment patient samples. In aggregate, our study describes time-dependent cellular, molecular, and regulatory effects for therapeutic inhibition of B cell receptor signaling in CLL, and it establishes a broadly applicable method for epigenome/transcriptome-based treatment monitoring.
Highlights
The Bruton tyrosine kinase (BTK) inhibitor ibrutinib provides effective treatment for patients with chronic lymphocytic leukemia (CLL), despite extensive heterogeneity in this disease
To investigate the cellular dynamics and regulatory program induced by the inhibition of B-cell receptor (BCR) signaling in CLL patients, we followed seven individuals from the start of ibrutinib therapy over a standardized time course of 240 days (Fig. 1a)
The progressive reduction in CLL cells coincided with an increase in the percentage of nonmalignant natural killer (NK) and T cell populations, consistent with a recent report[21]
Summary
The Bruton tyrosine kinase (BTK) inhibitor ibrutinib provides effective treatment for patients with chronic lymphocytic leukemia (CLL), despite extensive heterogeneity in this disease. To define the underlining regulatory dynamics, we analyze high-resolution time courses of ibrutinib treatment in patients with CLL, combining immune-phenotyping, single-cell transcriptome profiling, and chromatin mapping. Our study describes time-dependent cellular, molecular, and regulatory effects for therapeutic inhibition of B cell receptor signaling in CLL, and it establishes a broadly applicable method for epigenome/transcriptome-based treatment monitoring. Despite widespread clinical and molecular heterogeneity, therapeutic inhibition of BCR signaling using the Bruton tyrosine kinase (BTK) inhibitor ibrutinib[14] has remarkable efficacy in essentially all patients with CLL. Successful ibrutinib therapy often causes an initial increase of CLL cells in peripheral blood that can take months to resolve[19,20]. As the result of this ibrutinib-induced lymphocytosis, the correlation between the CLL cell count in peripheral blood and the clinical response to ibrutinib therapy is generally low[20], and there is an unmet need for early molecular markers of response to ibrutinib therapy
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