The targeting of human and mouse B lymphocytes by dasatinib

• Published in: Experimental hematology 2015-05, Vol.43 (5), p.352-363.e4
• Main Authors: Oksvold, Morten P, Duyvestyn, Johanna M, Dagger, Samantha A, Taylor, Samuel J, Forfang, Lise, Myklebust, June H, Smeland, Erlend B, Langdon, Wallace Y
• Format: Article
• Language: English
• Subjects: Advanced Basic Science; Agammaglobulinaemia Tyrosine Kinase; Animals; Antigens, CD19 - metabolism; Apoptosis - drug effects; B-Lymphocytes - drug effects; B-Lymphocytes - metabolism; Bone Marrow Cells - drug effects; Bone Marrow Cells - metabolism; Dasatinib; Flow Cytometry; Hematology, Oncology and Palliative Medicine; Humans; Male; Mice, Inbred C57BL; Phospholipase C gamma - antagonists & inhibitors; Phospholipase C gamma - metabolism; Precursor Cells, B-Lymphoid - drug effects; Precursor Cells, B-Lymphoid - metabolism; Protein Kinase Inhibitors - pharmacology; Protein-Tyrosine Kinases - antagonists & inhibitors; Protein-Tyrosine Kinases - metabolism; Pyrazoles - pharmacology; Pyrimidines - pharmacology; Receptors, Antigen, B-Cell - metabolism; Receptors, Antigen, T-Cell - metabolism; Signal Transduction - drug effects; Spleen - cytology; Spleen - drug effects; Spleen - metabolism; Thiazoles - pharmacology; Time Factors
• ISSN: 0301-472X; 1873-2399
• DOI: 10.1016/j.exphem.2015.01.008

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.