title: The spleen microenvironment influences disease transformation in a mouse model of KITD816V-dependent myeloproliferative neoplasm.
abstract: Activating mutations leading to ligand-independent signaling of the stem cell factor receptor KIT are associated with several hematopoietic malignancies. One of the most common alterations is the D816V mutation. In this study, we characterized mice, which conditionally express the humanized KITD816Vreceptor in the adult hematopoietic system to determine the pathological consequences of unrestrained KIT signaling during blood cell development. We found that KITD816Vmutant animals acquired a myeloproliferative neoplasm similar to polycythemia vera, marked by a massive increase in red blood cells and severe splenomegaly caused by excessive extramedullary erythropoiesis. Moreover, we found mobilization of stem cells from bone marrow to the spleen. Splenectomy prior to KITD816Vinduction prevented expansion of red blood cells, but rapidly lead to a state of aplastic anemia and bone marrow fibrosis, reminiscent of post polycythemic myeloid metaplasia, the spent phase of polycythemia vera. Our results show that the extramedullary hematopoietic niche microenvironment significantly influences disease outcome in KITD816Vmutant mice, turning this model a valuable tool for studying the interplay between functionally abnormal hematopoietic cells and their microenvironment during development of polycythemia vera-like disease and myelofibrosis.
authors.affiliation: University of Bonn Medical School, Institute of Pathology, Department of Developmental Pathology, 53127 Bonn, Germany.
authors.forename: Natalie
authors.initials: N
authors.lastname: Pelusi
authors.affiliation: Institute for Biomedical Engineering, Department of Cell Biology, RWTH Aachen University Medical School, Pauwelsstr. 30, 52074 Aachen, Germany.|Helmholtz Institute for Biomedical Engineering, RWTH Aachen University, Pauwelsstr. 20, 52074 Aachen, Germany.
authors.forename: Maike
authors.initials: M
authors.lastname: Kosanke
authors.affiliation: University of Bonn Medical School, Department of Internal Medicine III, Hematology and Oncology, Sigmund-Freud-Str. 25, 53127 Bonn, Germany.
authors.forename: Tamara
authors.initials: T
authors.lastname: Riedt
authors.affiliation: Institute for Biomedical Engineering, Department of Cell Biology, RWTH Aachen University Medical School, Pauwelsstr. 30, 52074 Aachen, Germany.|Helmholtz Institute for Biomedical Engineering, RWTH Aachen University, Pauwelsstr. 20, 52074 Aachen, Germany.
authors.forename: Corinna
authors.initials: C
authors.lastname: Rösseler
authors.affiliation: Institute for Biomedical Engineering, Department of Cell Biology, RWTH Aachen University Medical School, Pauwelsstr. 30, 52074 Aachen, Germany.|Helmholtz Institute for Biomedical Engineering, RWTH Aachen University, Pauwelsstr. 20, 52074 Aachen, Germany.
authors.forename: Kristin
authors.initials: K
authors.lastname: Seré
authors.affiliation: University of Bonn Medical School, Department of Internal Medicine III, Hematology and Oncology, Sigmund-Freud-Str. 25, 53127 Bonn, Germany.
authors.forename: Jin
authors.initials: J
authors.lastname: Li
authors.affiliation: University of Bonn Medical School, Institute of Pathology, Department of Developmental Pathology, 53127 Bonn, Germany.
authors.forename: Ines
authors.initials: I
authors.lastname: Gütgemann
authors.affiliation: Institute for Biomedical Engineering, Department of Cell Biology, RWTH Aachen University Medical School, Pauwelsstr. 30, 52074 Aachen, Germany.|Helmholtz Institute for Biomedical Engineering, RWTH Aachen University, Pauwelsstr. 20, 52074 Aachen, Germany.
authors.forename: Martin
authors.initials: M
authors.lastname: Zenke
authors.affiliation: University of Bonn Medical School, Department of Internal Medicine III, Hematology and Oncology, Sigmund-Freud-Str. 25, 53127 Bonn, Germany.
authors.forename: Viktor
authors.initials: V
authors.lastname: Janzen
authors.affiliation: University of Bonn Medical School, Institute of Pathology, Department of Developmental Pathology, 53127 Bonn, Germany.
authors.forename: Hubert
authors.initials: H
authors.lastname: Schorle
mesh_terms: D000818:Animals; D001854:Bone Marrow Cells / Q000473:pathology; D019046:Bone Marrow Neoplasms / Q000097:blood / Q000235:genetics* / Q000473:pathology*; D049109:Cell Proliferation; D002471:Cell Transformation, Neoplastic / Q000235:genetics / Q000473:pathology*; D004195:Disease Models, Animal; D004912:Erythrocytes / Q000378:metabolism / Q000473:pathology; D005355:Fibrosis; D050989:GATA2 Transcription Factor / Q000378:metabolism; D015972:Gene Expression Regulation, Neoplastic; D006410:Hematopoiesis; D006411:Hematopoiesis, Extramedullary; D006412:Hematopoietic Stem Cells / Q000378:metabolism; D008810:Mice, Inbred C57BL; D010641:Phenotype; D011087:Polycythemia Vera / Q000235:genetics / Q000473:pathology; D019009:Proto-Oncogene Proteins c-kit / Q000235:genetics*; D015398:Signal Transduction; D013154:Spleen / Q000473:pathology* / Q000601:surgery; D013163:Splenomegaly / Q000473:pathology; D059016:Tumor Microenvironment
chemical_list: D050989:GATA2 Transcription Factor; D019009:Proto-Oncogene Proteins c-kit