title: Inactivation of the tumor suppressor gene von Hippel-Lindau (VHL) in granulocytes contributes to development of liver hemangiomas in a mouse model.
abstract: Mutations in the tumor suppressor gene von Hippel-Lindau (VHL) underlie a hereditary cancer syndrome-VHL disease-and are also frequently observed in sporadic renal cell carcinoma of the clear cell type (ccRCC). VHL disease is characterized by malignant and benign tumors in a few specific tissues, including ccRCC, hemangioblastoma and pheochromocytoma. The etiology of these tumors remains unresolved.
  
  
  
  Conditional inactivation of the VHL gene in mouse (Vhlh) was generated to examine the pathophysiological role of the VHL gene function. Specific cell populations were isolated by fluorescence-activated cell sorting (FACS) and bone marrow transplants were performed to identify the Vhlh-inactivated cells responsible for the phenotype.
  
  
  
  Previously we showed that inactivation of Vhlh in a subpopulation of kidney distal tubule cells resulted in hyperplastic clear-cell lesions and severe inflammation and fibrosis. Here, we show that this knockout mouse strain also develops Hif-2α-dependent vascular overgrowth (hemangioma) and extramedullary erythropoiesis in the liver. However, Vhlh inactivation was not detected in the liver parenchyma. We instead demonstrate that in these mice, Vhlh is inactivated in liver granulocytes and that hemangiomas are partially rescued in knockout mice reconstituted with wild-type hematopoietic stem cells, indicating the involvement of bone-marrow-derived leukocyte. Interestingly, bone marrow from knockout mice failed to generate the liver phenotype in wild-type recipients, suggesting that an additional cell type that is not derived from the bone marrow is involved in the development of the hemangioma phenotype.
  
  
  
  These results support the idea that the development of a full-blown VHL disease phenotype requires inactivation of the VHL gene not only in the tumor proper, but also in the stromal compartment.
authors.affiliation: Department of Medicine, Boston University School of Medicine, Boston, MA, USA. baderh@bu.edu.
authors.forename: Hannah L
authors.initials: HL
authors.lastname: Bader
authors.affiliation: Department of Medicine, Boston University School of Medicine, Boston, MA, USA. tienhsu@ncu.edu.tw.|Department of Biomedical Sciences and Engineering, National Central University, Chung-li, Taiwan. tienhsu@ncu.edu.tw.
authors.forename: Tien
authors.identifier: 0000-0003-2308-4297
authors.initials: T
authors.lastname: Hsu
mesh_terms: D000818:Animals; D015415:Biomarkers; D004195:Disease Models, Animal; D004921:Erythropoietin / Q000097:blood / Q000378:metabolism; D005434:Flow Cytometry; D020868:Gene Silencing; D006098:Granulocytes / Q000378:metabolism*; D006391:Hemangioma / Q000235:genetics* / Q000378:metabolism / Q000473:pathology; D006411:Hematopoiesis, Extramedullary / Q000235:genetics; D006412:Hematopoietic Stem Cells / Q000166:cytology / Q000378:metabolism; D018398:Homeodomain Proteins / Q000235:genetics; D007962:Leukocytes / Q000378:metabolism / Q000473:pathology; D008099:Liver / Q000378:metabolism / Q000473:pathology; D008113:Liver Neoplasms / Q000235:genetics* / Q000378:metabolism / Q000473:pathology; D051379:Mice; D018345:Mice, Knockout; D009154:Mutation; D010641:Phenotype; D051794:Von Hippel-Lindau Tumor Suppressor Protein / Q000235:genetics*
chemical_list: D015415:Biomarkers; D018398:Homeodomain Proteins; C093253:Hoxb7 protein, mouse; D004921:Erythropoietin; D051794:Von Hippel-Lindau Tumor Suppressor Protein
keywords: Angiogenesis; Extramedullary erythropoiesis; Hemangioblastoma; Hemangioma; Hypoxia-inducible factor 2 alpha; Neutrophil; Placental growth factor; von Hippel-Lindau