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A Chromatin Immunoprecipitation Assay to Identify Novel NFAT2 Target Genes in Chronic Lymphocytic Leukemia
Published on: December 4, 2018
Single cell immune profiling by mass cytometry of newly diagnosed chronic phase chronic myeloid leukemia treated with
Stein-Erik Gullaksen1, Jørn Skavland1, Sonia Gavasso2,3
1Centre of Cancer Biomarkers CCBIO, Department of Clinical Science, Precision Oncology Research Group, University of Bergen, Norway.
Abstract:
Monitoring of single cell signal transduction in leukemic cellular subsets has been proposed to provide deeper understanding of disease biology and prognosis, but has so far not been tested in a clinical trial of targeted therapy. We developed a complete mass cytometry analysis pipeline for characterization of intracellular signal transduction patterns in the major leukocyte subsets of chronic phase chronic myeloid leukemia. Changes in phosphorylated Bcr-Abl1 and the signaling pathways involved were readily identifiable in peripheral blood single cells already within three hours of the patient receiving oral nilotinib. The signal transduction profiles of healthy donors were clearly distinct from those of the patients at diagnosis. Furthermore, using principal component analysis, we could show that phosphorylated transcription factors STAT3 (Y705) and CREB (S133) within seven days reflected BCR-ABL1IS at three and six months. Analyses of peripheral blood cells longitudinally collected from patients in the ENEST1st clinical trial showed that single cell mass cytometry appears to be highly suitable for future investigations addressing tyrosine kinase inhibitor dosing and effect. (clinicaltrials.gov identifier: 01061177).
Insights
Mass cytometry monitoring of single cells in chronic myeloid leukemia reveals rapid drug effects and distinct patient profiles. This method shows promise for optimizing targeted therapy and tyrosine kinase inhibitor dosing.
Area of Science:
- Hematology
- Oncology
- Immunology
Background:
- Single cell signal transduction monitoring offers insights into leukemia biology and prognosis.
- Clinical application in targeted therapy trials has been limited.
Purpose of the Study:
- To develop and validate a mass cytometry pipeline for analyzing intracellular signaling in chronic myeloid leukemia (CML).
- To assess the utility of this method in a clinical trial setting for tyrosine kinase inhibitor (TKI) therapy.
Main Methods:
- Developed a mass cytometry analysis pipeline for peripheral blood leukocyte subsets.
- Analyzed intracellular signal transduction patterns, including phosphorylated Bcr-Abl1, STAT3, and CREB.
- Utilized principal component analysis for longitudinal data analysis in the ENEST1st clinical trial.
Main Results:
- Identified rapid changes in phosphorylated Bcr-Abl1 and signaling pathways within three hours of nilotinib administration.
- Demonstrated distinct signal transduction profiles between CML patients at diagnosis and healthy donors.
- Showed that phosphorylated STAT3 and CREB levels correlated with BCR-ABL1IS levels over time.
Conclusions:
- Single cell mass cytometry is a sensitive tool for monitoring TKI effects in CML.
- This approach can differentiate patient and healthy donor profiles and track treatment response.
- The method holds potential for optimizing TKI dosing and evaluating treatment efficacy in clinical settings.
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