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The targeting of human and mouse B lymphocytes by dasatinib
Morten P Oksvold1, Johanna M Duyvestyn2, Samantha A Dagger2
1Department of Immunology, Institute for Cancer Research, Oslo University Hospital, Oslo, Norway; Centre for Cancer Biomedicine, University of Oslo, Oslo, Norway.
Abstract:
Dasatinib inhibits B-cell receptor-Abelson murine leukemia viral oncogene homologue 1, Src, and other tyrosine kinases. Few studies have addressed the impact of dasatinib on normal blood cells, especially in vivo. Here we show that dasatinib leads to a reduced number of human CD19+ peripheral B cells owing to a strong induction of apoptosis. In contrast, no similar effect on T-cell viability was observed. However, dasatinib induced a comparable broad inhibition of the early events of B- and T-cell receptor signaling. Furthermore, dasatinib was shown to be a more pronounced inhibitor of both basal and B-cell receptor-induced activity of Bruton's tyrosine kinase and PLCγ2 compared with the more specific Bruton's tyrosine kinase inhibitor ibrutinib. Human progenitor B cells from the pre-B stage were sensitive to dasatinib. In an in vivo murine model, dasatinib reduced B-lineage cells in the bone marrow with a marked effect on the pre-B subpopulation. Dasatinib led to a reduced spleen size, with a loss of large immature transitional immunoglobulin M(+)/immunoglobulin D(-) B cells and a reduction in germinal center B cells. Dasatinib caused a marked loss of thymocytes without affecting myeloid lineage cells or hematopoietic progenitors. This study reveals important side effects of dasatinib with specific loss of activated B and thymocyte populations, which may have an impact during long-term treatment.
Insights
Dasatinib significantly reduces peripheral B cells and thymocytes by inducing apoptosis, impacting B-cell receptor signaling. This tyrosine kinase inhibitor affects normal blood cells, particularly B-cell populations, in vivo.
Area of Science:
- Immunology
- Pharmacology
- Hematology
Background:
- Dasatinib is a tyrosine kinase inhibitor used in cancer therapy.
- Its effects on normal blood cells, especially in vivo, are not well-documented.
- Understanding dasatinib's impact on healthy immune cells is crucial for managing treatment side effects.
Purpose of the Study:
- To investigate the in vivo effects of dasatinib on normal human B cells and T cells.
- To compare dasatinib's inhibitory effects on B-cell receptor signaling with ibrutinib.
- To identify specific populations of lymphocytes affected by dasatinib treatment.
Main Methods:
- Treatment of human peripheral blood cells with dasatinib.
- Assessment of apoptosis and cell viability in B and T cells.
- Analysis of B-cell receptor and T-cell receptor signaling pathways.
- In vivo studies using a murine model to evaluate dasatinib's effects on bone marrow and spleen.
Main Results:
- Dasatinib induced significant apoptosis in CD19+ peripheral B cells but not T cells.
- It broadly inhibited early signaling events in both B- and T-cell receptors.
- Dasatinib demonstrated greater inhibition of Bruton's tyrosine kinase and PLCγ2 compared to ibrutinib.
- In vivo, dasatinib reduced B-lineage cells in bone marrow and spleen, including transitional and germinal center B cells, and thymocytes, without affecting myeloid cells.
Conclusions:
- Dasatinib causes a specific loss of activated B cells and thymocytes.
- The drug impacts normal hematopoiesis, with notable effects on B-cell development and survival.
- These findings highlight potential side effects of dasatinib, relevant for long-term patient management.
