Long-term treatment with imatinib results in profound mast cell deficiency in Ph+ chronic myeloid leukemia

Sabine Cerny-Reiterer, Anja Rabenhorst, Gabriele Stefanzl, Susanne Herndlhofer, Gregor Hoermann, Leonhard Müllauer, Sigrid Baumgartner, Christine Beham-Schmid, Wolfgang R. Sperr, Christine Mannhalter, Heinz Sill, Werner Linkesch, Michel Arock, Karin Hartmann, Peter Valent*

*Korrespondierende/r Autor/-in für diese Arbeit
13 Zitate (Scopus)

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 MCdevelopment 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.
OriginalspracheEnglisch
ZeitschriftOncotarget
Jahrgang6
Ausgabenummer5
Seiten (von - bis)3071-3084
Seitenumfang14
DOIs
PublikationsstatusVeröffentlicht - 01.01.2015

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