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Updated: Dec 29, 2025
Immunoglobulin Gene Sequence Analysis In Chronic Lymphocytic Leukemia: From Patient Material To Sequence Interpretation
Published on: November 26, 2018
Chromatin mapping and single-cell immune profiling define the temporal dynamics of ibrutinib response in CLL
André F Rendeiro1, Thomas Krausgruber1, Nikolaus Fortelny1
1CeMM Research Center for Molecular Medicine of the Austrian Academy of Sciences, Vienna, Austria.
Insights
Ibrutinib treatment for chronic lymphocytic leukemia (CLL) triggers a consistent regulatory program. This program involves decreased NF-κB binding, altered transcription factor activity, and a shift towards cell quiescence, with variable patient responses.
Area of Science:
- Oncology
- Immunology
- Molecular Biology
Background:
- Chronic lymphocytic leukemia (CLL) exhibits significant heterogeneity.
- Bruton tyrosine kinase (BTK) inhibitors like ibrutinib are effective CLL treatments.
Purpose of the Study:
- To define the regulatory dynamics of ibrutinib treatment in CLL.
- To identify patient-specific responses to ibrutinib therapy.
Main Methods:
- High-resolution time-course analysis of ibrutinib treatment in CLL patients.
- Integration of immune-phenotyping, single-cell transcriptome profiling, and chromatin mapping.
- Analysis of NF-κB binding and lineage-defining transcription factor activity.
Main Results:
- A consistent regulatory program was identified, initiated by decreased NF-κB binding.
- This program involves reduced transcription factor activity, CLL cell identity erosion, and a quiescence-like gene signature.
- Patient-specific variations in response speed were observed and used for predictive modeling.
Conclusions:
- Ibrutinib therapy induces time-dependent cellular and molecular changes in CLL by inhibiting B cell receptor signaling.
- A broadly applicable method for epigenome/transcriptome-based treatment monitoring was established.
- Understanding these dynamics aids in predicting and personalizing CLL treatment.
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.
