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

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 imatin...

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Autores principales: Cerny-Reiterer, Sabine, Rabenhorst, Anja, Stefanzl, Gabriele, Herndlhofer, Susanne, Hoermann, Gregor, Müllauer, Leonhard, Baumgartner, Sigrid, Beham-Schmid, Christine, Sperr, Wolfgang R, Mannhalter, Christine, Sill, Heinz, Linkesch, Werner, Arock, Michel, Hartmann, Karin, Valent, Peter
Formato: Online Artículo Texto
Lenguaje:English
Publicado: Impact Journals LLC 2014
Materias:
Acceso en línea:https://www.ncbi.nlm.nih.gov/pmc/articles/PMC4413638/
https://www.ncbi.nlm.nih.gov/pubmed/25605011
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author Cerny-Reiterer, Sabine
Rabenhorst, Anja
Stefanzl, Gabriele
Herndlhofer, Susanne
Hoermann, Gregor
Müllauer, Leonhard
Baumgartner, Sigrid
Beham-Schmid, Christine
Sperr, Wolfgang R
Mannhalter, Christine
Sill, Heinz
Linkesch, Werner
Arock, Michel
Hartmann, Karin
Valent, Peter
author_facet Cerny-Reiterer, Sabine
Rabenhorst, Anja
Stefanzl, Gabriele
Herndlhofer, Susanne
Hoermann, Gregor
Müllauer, Leonhard
Baumgartner, Sigrid
Beham-Schmid, Christine
Sperr, Wolfgang R
Mannhalter, Christine
Sill, Heinz
Linkesch, Werner
Arock, Michel
Hartmann, Karin
Valent, Peter
author_sort Cerny-Reiterer, Sabine
collection PubMed
description 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.
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spelling pubmed-44136382015-05-08 Long-term treatment with imatinib results in profound mast cell deficiency in Ph+ chronic myeloid leukemia Cerny-Reiterer, Sabine Rabenhorst, Anja Stefanzl, Gabriele Herndlhofer, Susanne Hoermann, Gregor Müllauer, Leonhard Baumgartner, Sigrid Beham-Schmid, Christine Sperr, Wolfgang R Mannhalter, Christine Sill, Heinz Linkesch, Werner Arock, Michel Hartmann, Karin Valent, Peter Oncotarget Research Paper 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. Impact Journals LLC 2014-12-26 /pmc/articles/PMC4413638/ /pubmed/25605011 Text en Copyright: © 2015 Cerny-Reiterer et al. http://creativecommons.org/licenses/by/2.5/ This is an open-access article distributed under the terms of the Creative Commons Attribution License, which permits unrestricted use, distribution, and reproduction in any medium, provided the original author and source are credited.
spellingShingle Research Paper
Cerny-Reiterer, Sabine
Rabenhorst, Anja
Stefanzl, Gabriele
Herndlhofer, Susanne
Hoermann, Gregor
Müllauer, Leonhard
Baumgartner, Sigrid
Beham-Schmid, Christine
Sperr, Wolfgang R
Mannhalter, Christine
Sill, Heinz
Linkesch, Werner
Arock, Michel
Hartmann, Karin
Valent, Peter
Long-term treatment with imatinib results in profound mast cell deficiency in Ph+ chronic myeloid leukemia
title Long-term treatment with imatinib results in profound mast cell deficiency in Ph+ chronic myeloid leukemia
title_full Long-term treatment with imatinib results in profound mast cell deficiency in Ph+ chronic myeloid leukemia
title_fullStr Long-term treatment with imatinib results in profound mast cell deficiency in Ph+ chronic myeloid leukemia
title_full_unstemmed Long-term treatment with imatinib results in profound mast cell deficiency in Ph+ chronic myeloid leukemia
title_short Long-term treatment with imatinib results in profound mast cell deficiency in Ph+ chronic myeloid leukemia
title_sort long-term treatment with imatinib results in profound mast cell deficiency in ph+ chronic myeloid leukemia
topic Research Paper
url https://www.ncbi.nlm.nih.gov/pmc/articles/PMC4413638/
https://www.ncbi.nlm.nih.gov/pubmed/25605011
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