Long-term treatment with imatinib results in profound mast cell deficiency in Ph+ chronic myeloid leukemia
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Sabine Cerny-Reiterer1,2, Anja Rabenhorst3, Gabriele Stefanzl2, Susanne Herndlhofer2, Gregor Hoermann4, Leonhard Müllauer5, Sigrid Baumgartner6, Christine Beham-Schmid7, Wolfgang R. Sperr1,2, Christine Mannhalter4, Heinz Sill8, Werner Linkesch8, Michel Arock9, Karin Hartmann3 and Peter Valent1,2
1 Ludwig Boltzmann Cluster Oncology, Medical University of Vienna, Austria
2 Department of Internal Medicine I, Division of Hematology and Hemostaseology, Medical University of Vienna, Austria
3 Department of Dermatology, University of Cologne, Cologne, Germany
4 Department of Laboratory Medicine, Medical University of Vienna, Austria
5 Department of Pathology, Medical University of Vienna, Austria
6 Department of Pediatrics and Adolescent Medicine, Medical University of Vienna, Austria
7 Institute of Pathology, Medical University of Graz, Austria
8 Department of Internal Medicine, Division of Hematology, Medical University of Graz, Austria
9 LBPA CNRS UMR8113, Ecole Normale Supérieure de Cachan, Cachan, France
Peter Valent, email:
Keywords: Mast Cells, KIT, Imatinib, Mast Cell Deficiency
Received: October 31, 2014 Accepted: December 17, 2014 Published: December 26, 2014
Although mast cells (MC) play an important role in allergic reactions, their physiologic role remains unknown. In mice, several models of MC-deficiency have been developed. However, no comparable human model is available. We examined the in vitro- and in vivo effects of the KIT-targeting drug imatinib on growth and development of human MC. Imatinib was found to inhibit stem cell factor (SCF)-induced differentiation of MC in long-term suspension cultures (IC50: 0.01 µM). Correspondingly, long-term treatment of chronic myeloid leukemia (CML) patients with imatinib (400 mg/day) resulted in a marked decrease in MC. In patients with continuous complete molecular response during therapy, bone marrow MC decreased to less than 5% of pre-treatment values, and also serum tryptase concentrations decreased significantly (pre-treatment: 32.0±11.1 ng/ml; post-therapy: 3.4±1.8, p<0.01). Other myeloid lineages, known to develop independently of KIT, were not affected by imatinib-therapy. Imatinib also produced a substantial decrease in MC-development in mice. However, no clinical syndrome attributable to drug-induced MC-deficiency was recorded in our CML patients. Together, imatinib suppresses MC production in vitro and in vivo. However, drug-induced MC depletion is not accompanied by adverse clinical events, suggesting that MC are less relevant to homeostasis in healthy tissues than we assumed so far.
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