title: P-Selectin Sustains Extramedullary Hematopoiesis in the Gata1 low Model of Myelofibrosis.
abstract: Splenomegaly is a major manifestation of primary myelofibrosis (PMF) contributing to clinical symptoms and hematologic abnormalities. The spleen from PMF patients contains increased numbers of hematopoietic stem cells (HSC) and megakaryocytes (MK). These MK express high levels of P-selectin (P-sel) that, by triggering neutrophil emperipolesis, may cause TGF-β release and disease progression. This hypothesis was tested by deleting the P-sel gene in the myelofibrosis mouse model carrying the hypomorphic Gata1(low) mutation that induces megakaryocyte abnormalities that recapitulate those observed in PMF. P-sel(null) Gata1(low) mice survived splenectomy and lived 3 months longer than P-sel(WT) Gata1(low) littermates and expressed limited fibrosis and osteosclerosis in the marrow or splenomegaly. Furthermore, deletion of P-sel disrupted megakaryocyte/neutrophil interactions in spleen, reduced TGF-β content, and corrected the HSC distribution that in Gata1(low) mice, as in PMF patients, is abnormally expanded in spleen. Conversely, pharmacological inhibition of TGF-β reduced P-sel expression in MK and corrected HSC distribution. Spleens, but not marrow, of Gata1(low) mice contained numerous cKIT(pos) activated fibrocytes, probably of dendritic cell origin, whose membrane protrusions interacted with MK establishing niches hosting immature cKIT(pos) hematopoietic cells. These activated fibrocytes were not detected in spleens from P-sel(null) Gata1(low) or TGF-β-inhibited Gata1(low) littermates and were observed in spleen, but not in marrow, from PMF patients. Therefore, in Gata1(low) mice, and possibly in PMF, abnormal P-sel expression in MK may mediate the pathological cell interactions that increase TGF-β content in MK and favor establishment of a microenvironment that supports myelofibrosis-related HSC in spleen.
authors.affiliation: Department of Medicine, Division of Hematology and Hematologic Malignancies, University of Utah, Salt Lake City, Utah, USA.
authors.forename: Gerald J
authors.initials: GJ
authors.lastname: Spangrude
authors.affiliation: CEA/DSV/iRCM/LRTS, Inserm U967, Fontenay-aux-Roses Cedex, Paris, France.
authors.forename: Daniel
authors.initials: D
authors.lastname: Lewandowski
authors.affiliation: Department of Hematology, Oncology and Molecular Medicine, Istituto Superiore di Sanità
authors.forename: Fabrizio
authors.initials: F
authors.lastname: Martelli
authors.affiliation: Department of Hematology, Oncology and Molecular Medicine, Istituto Superiore di Sanità
authors.forename: Manuela
authors.initials: M
authors.lastname: Marra
authors.affiliation: Department of Medicine, Campus Biomedico, Rome, Italy.
authors.forename: Maria
authors.initials: M
authors.lastname: Zingariello
authors.affiliation: Istituto Genetica Medica, Centro Nazionale Ricerche, and Medicine and Aging Sciences, Section of Human Momorphology, University G. D'Annunzio, Chieti, Italy.
authors.forename: Laura
authors.initials: L
authors.lastname: Sancillo
authors.affiliation: Istituto Genetica Medica, Centro Nazionale Ricerche, and Medicine and Aging Sciences, Section of Human Momorphology, University G. D'Annunzio, Chieti, Italy.
authors.forename: Rosa Alba
authors.initials: RA
authors.lastname: Rana
authors.affiliation: Department of Biomedical Sciences, Alma Mater University, Bologna, Italy.|Tisch Cancer Institute, Mount Sinai School of Medicine, New York, New York, USA.
authors.forename: Anna Rita
authors.initials: AR
authors.lastname: Migliaccio
mesh_terms: D000818:Animals; D002454:Cell Differentiation; D004195:Disease Models, Animal; D057687:Emperipolesis; D005260:Female; D050982:GATA1 Transcription Factor / Q000378:metabolism*; D006411:Hematopoiesis, Extramedullary; D006801:Humans; D008297:Male; D008533:Megakaryocytes / Q000473:pathology / Q000648:ultrastructure; D051379:Mice; D009504:Neutrophils / Q000378:metabolism; D019007:P-Selectin / Q000378:metabolism*; D010641:Phenotype; D055728:Primary Myelofibrosis / Q000378:metabolism* / Q000473:pathology; D013154:Spleen / Q000473:pathology / Q000648:ultrastructure; D016212:Transforming Growth Factor beta / Q000378:metabolism
chemical_list: D050982:GATA1 Transcription Factor; D019007:P-Selectin; D016212:Transforming Growth Factor beta
keywords: Activated fibrocytes; Extramedullary hematopoiesis; Megakaryocytes; Myelofibrosis-related stem cells; P-selectin; TGF-β