title: Interleukin-9 (IL-9) and NPM-ALK each generate mast cell hyperplasia as single 'hit' and cooperate in producing a mastocytosis-like disease in mice.
abstract: Mast cell neoplasms are characterized by abnormal growth and focal accumulation of mast cells (MC) in one or more organs. Although several cytokines, including stem cell factor (SCF) and interleukin-9 (IL-9) have been implicated in growth of normal MC, little is known about pro-oncogenic molecules and conditions triggering differentiation and growth of MC far enough to lead to the histopathological picture of overt mastocytosis. The anaplastic lymphoma kinase (ALK) has recently been implicated in growth of neoplastic cells in malignant lymphomas. Here, we describe that transplantation of NPM-ALK-transplanted mouse bone marrow progenitors into lethally irradiated IL-9 transgenic mice not only results in lymphoma-formation, but also in the development of a neoplastic disease exhibiting histopathological features of systemic mastocytosis, including multifocal dense MC-infiltrates, occasionally with devastating growth in visceral organs. Transplantation of NPM-ALK-transduced progenitors into normal mice or maintenance of IL-9-transgenic mice without NPM-ALK each resulted in MC hyperplasia, but not in mastocytosis. Neoplastic MC in mice not only displayed IL-9, but also the IL-9 receptor, and the same was found to hold true for human neoplastic MC. Together, our data show that neoplastic MC express IL-9 receptors, that IL-9 and NPM-ALK upregulate MC-production in vivo, and that both'hits' act in concert to induce a mastocytosis-like disease in mice. These data may have pathogenetic and clinical implications and fit well with the observation that neoplastic MC in advanced SM strongly express NPM and multiple "lymphoid" antigens including CD25 and CD30.
authors.affiliation: Department of Pathology, Medical University of Schleswig-Holstein, Campus Luebeck, Luebeck, Germany.
authors.forename: Hartmut
authors.initials: H
authors.lastname: Merz
authors.affiliation: Department of Pathology, Medical University of Schleswig-Holstein, Campus Luebeck, Luebeck, Germany.
authors.forename: Christian
authors.initials: C
authors.lastname: Kaehler
authors.affiliation: Institute for Molecular Immunology, Helmholtz Zentrum München, Germany.
authors.forename: Kai P
authors.initials: KP
authors.lastname: Hoefig
authors.affiliation: Department of Pathology, Medical University of Schleswig-Holstein, Campus Luebeck, Luebeck, Germany.
authors.forename: Biggi
authors.initials: B
authors.lastname: Branke
authors.affiliation: Max-Delbrueck-Center for Molecular Medicine, Berlin, Germany.
authors.forename: Wolfgang
authors.initials: W
authors.lastname: Uckert
authors.affiliation: Institute for Radiotherapy, Medical University of Schleswig-Holstein, Campus Lübeck, Luebeck, Germany.
authors.forename: Roger
authors.initials: R
authors.lastname: Nadrowitz
authors.affiliation: Department of Medicine I, Division of Hematology, Medical University of Vienna, Austria.
authors.forename: Sabine
authors.initials: S
authors.lastname: Cerny-Reiterer
authors.affiliation: Ludwig Boltzmann Cluster Oncology, Vienna, Austria.
authors.forename: Harald
authors.initials: H
authors.lastname: Herrmann
authors.affiliation: Department of Pathology, Medical University of Schleswig-Holstein, Campus Luebeck, Luebeck, Germany.
authors.forename: Alfred C
authors.initials: AC
authors.lastname: Feller
authors.affiliation: Department of Medicine I, Division of Hematology, Medical University of Vienna, Austria.|Ludwig Boltzmann Cluster Oncology, Vienna, Austria.
authors.forename: Peter
authors.initials: P
authors.lastname: Valent
mesh_terms: D000077548:Anaplastic Lymphoma Kinase; D000818:Animals; D016026:Bone Marrow Transplantation; D045744:Cell Line, Tumor; D005260:Female; D005434:Flow Cytometry; D006801:Humans; D006965:Hyperplasia; D053645:Interleukin-2 Receptor alpha Subunit / Q000032:analysis; D016906:Interleukin-9 / Q000235:genetics / Q000378:metabolism*; D017730:Ki-1 Antigen / Q000032:analysis; D008297:Male; D008407:Mast Cells / Q000276:immunology / Q000378:metabolism / Q000473:pathology*; D034721:Mastocytosis, Systemic / Q000378:metabolism / Q000473:pathology*; D051379:Mice; D008822:Mice, Transgenic; D009687:Nuclear Proteins / Q000235:genetics; D000090243:Nucleophosmin; D015514:Oncogene Proteins, Fusion / Q000235:genetics / Q000378:metabolism*; D016133:Polymerase Chain Reaction; D011505:Protein-Tyrosine Kinases / Q000235:genetics / Q000378:metabolism*; D012333:RNA, Messenger / Q000235:genetics / Q000378:metabolism; D020794:Receptor Protein-Tyrosine Kinases / Q000235:genetics; D053651:Receptors, Interleukin-9 / Q000235:genetics / Q000378:metabolism*; D019089:Stem Cell Factor / Q000378:metabolism
chemical_list: D053645:Interleukin-2 Receptor alpha Subunit; D016906:Interleukin-9; D017730:Ki-1 Antigen; D009687:Nuclear Proteins; D015514:Oncogene Proteins, Fusion; D012333:RNA, Messenger; D053651:Receptors, Interleukin-9; D019089:Stem Cell Factor; D000090243:Nucleophosmin; C107023:p80(NPM-ALK) protein; C000626173:ALK protein, human; C000626174:Alk protein, mouse; D000077548:Anaplastic Lymphoma Kinase; D011505:Protein-Tyrosine Kinases; D020794:Receptor Protein-Tyrosine Kinases