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.
