title: Long-term treatment with imatinib results in profound mast cell deficiency in Ph+ chronic myeloid leukemia.
abstract: 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.
authors.affiliation: Ludwig Boltzmann Cluster Oncology, Medical University of Vienna, Austria.|Department of Internal Medicine I, Division of Hematology and Hemostaseology, Medical University of Vienna, Austria.
authors.forename: Sabine
authors.initials: S
authors.lastname: Cerny-Reiterer
authors.affiliation: Department of Dermatology, University of Cologne, Cologne, Germany.
authors.forename: Anja
authors.initials: A
authors.lastname: Rabenhorst
authors.affiliation: Department of Internal Medicine I, Division of Hematology and Hemostaseology, Medical University of Vienna, Austria.
authors.forename: Gabriele
authors.initials: G
authors.lastname: Stefanzl
authors.affiliation: Department of Internal Medicine I, Division of Hematology and Hemostaseology, Medical University of Vienna, Austria.
authors.forename: Susanne
authors.initials: S
authors.lastname: Herndlhofer
authors.affiliation: Department of Laboratory Medicine, Medical University of Vienna, Austria.
authors.forename: Gregor
authors.initials: G
authors.lastname: Hoermann
authors.affiliation: Department of Pathology, Medical University of Vienna, Austria.
authors.forename: Leonhard
authors.initials: L
authors.lastname: Müllauer
authors.affiliation: Department of Pediatrics and Adolescent Medicine, Medical University of Vienna, Austria.
authors.forename: Sigrid
authors.initials: S
authors.lastname: Baumgartner
authors.affiliation: Institute of Pathology, Medical University of Graz, Austria.
authors.forename: Christine
authors.initials: C
authors.lastname: Beham-Schmid
authors.affiliation: Ludwig Boltzmann Cluster Oncology, Medical University of Vienna, Austria.|Department of Internal Medicine I, Division of Hematology and Hemostaseology, Medical University of Vienna, Austria.
authors.forename: Wolfgang R
authors.initials: WR
authors.lastname: Sperr
authors.affiliation: Department of Laboratory Medicine, Medical University of Vienna, Austria.
authors.forename: Christine
authors.initials: C
authors.lastname: Mannhalter
authors.affiliation: Department of Internal Medicine, Division of Hematology, Medical University of Graz, Austria.
authors.forename: Heinz
authors.initials: H
authors.lastname: Sill
authors.affiliation: Department of Internal Medicine, Division of Hematology, Medical University of Graz, Austria.
authors.forename: Werner
authors.initials: W
authors.lastname: Linkesch
authors.affiliation: LBPA CNRS UMR8113, Ecole Normale Supérieure de Cachan, Cachan, France.
authors.forename: Michel
authors.initials: M
authors.lastname: Arock
authors.affiliation: Department of Dermatology, University of Cologne, Cologne, Germany.
authors.forename: Karin
authors.initials: K
authors.lastname: Hartmann
authors.affiliation: Ludwig Boltzmann Cluster Oncology, Medical University of Vienna, Austria.|Department of Internal Medicine I, Division of Hematology and Hemostaseology, Medical University of Vienna, Austria.
authors.forename: Peter
authors.initials: P
authors.lastname: Valent
mesh_terms: D000328:Adult; D000368:Aged; D000818:Animals; D000970:Antineoplastic Agents / Q000009:adverse effects*; D045744:Cell Line, Tumor; D004305:Dose-Response Relationship, Drug; D005260:Female; D015971:Gene Expression Regulation, Enzymologic; D015972:Gene Expression Regulation, Neoplastic; D006801:Humans; D000068877:Imatinib Mesylate / Q000009:adverse effects*; D015464:Leukemia, Myelogenous, Chronic, BCR-ABL Positive / Q000188:drug therapy* / Q000201:enzymology / Q000235:genetics / Q000276:immunology; D008297:Male; D008407:Mast Cells / Q000187:drug effects* / Q000201:enzymology / Q000276:immunology; D008807:Mice, Inbred BALB C; D008810:Mice, Inbred C57BL; D008875:Middle Aged; D047428:Protein Kinase Inhibitors / Q000009:adverse effects*; D019009:Proto-Oncogene Proteins c-kit / Q000037:antagonists & inhibitors* / Q000235:genetics / Q000378:metabolism; D013997:Time Factors; D016896:Treatment Outcome; D053802:Tryptases / Q000235:genetics / Q000378:metabolism; D023041:Xenograft Model Antitumor Assays
chemical_list: D000970:Antineoplastic Agents; D047428:Protein Kinase Inhibitors; D000068877:Imatinib Mesylate; D019009:Proto-Oncogene Proteins c-kit; D053802:Tryptases