title: Stromal SPARC contributes to the detrimental fibrotic changes associated with myeloproliferation whereas its deficiency favors myeloid cell expansion.
abstract: In myeloid malignancies, the neoplastic clone outgrows normal hematopoietic cells toward BM failure. This event is also sustained by detrimental stromal changes, such as BM fibrosis and osteosclerosis, whose occurrence is harbinger of a dismal prognosis. We show that the matricellular protein SPARC contributes to the BM stromal response to myeloproliferation. The degree of SPARC expression in BM stromal elements, including CD146(+) mesenchymal stromal cells, correlates with the degree of stromal changes, and the severity of BM failure characterizing the prototypical myeloproliferative neoplasm primary myelofibrosis. Using Sparc(-/-) mice and BM chimeras, we demonstrate that SPARC contributes to the development of significant stromal fibrosis in a model of thrombopoietin-induced myelofibrosis. We found that SPARC deficiency in the radioresistant BM stroma compartment impairs myelofibrosis but, at the same time, associates with an enhanced reactive myeloproliferative response to thrombopoietin. The link betwen SPARC stromal deficiency and enhanced myeloid cell expansion under a myeloproliferative spur is also supported by the myeloproliferative phenotype resulting from the transplantation of defective Apc(min) mutant hematopoietic cells into Sparc(-/-) but not WT recipient BM stroma. Our results highlight a complex influence of SPARC over the stromal and hematopoietic BM response in myeloproliferative conditions.
authors.affiliation: Tumor Immunology Unit, Human Pathology Section, Department of Health Sciences, University of Palermo, Italy. claudio.tripodo@unipa.it
authors.forename: Claudio
authors.initials: C
authors.lastname: Tripodo
authors.forename: Sabina
authors.initials: S
authors.lastname: Sangaletti
authors.forename: Carla
authors.initials: C
authors.lastname: Guarnotta
authors.forename: Pier P
authors.initials: PP
authors.lastname: Piccaluga
authors.forename: Matilde
authors.initials: M
authors.lastname: Cacciatore
authors.forename: Michela
authors.initials: M
authors.lastname: Giuliano
authors.forename: Giovanni
authors.initials: G
authors.lastname: Franco
authors.forename: Claudia
authors.initials: C
authors.lastname: Chiodoni
authors.forename: Marika
authors.initials: M
authors.lastname: Sciandra
authors.forename: Silvia
authors.initials: S
authors.lastname: Miotti
authors.forename: Giuseppe
authors.initials: G
authors.lastname: Calvaruso
authors.forename: Alessandra
authors.initials: A
authors.lastname: Carè
authors.forename: Ada M
authors.initials: AM
authors.lastname: Florena
authors.forename: Katia
authors.initials: K
authors.lastname: Scotlandi
authors.forename: Attilio
authors.initials: A
authors.lastname: Orazi
authors.forename: Stefano A
authors.initials: SA
authors.lastname: Pileri
authors.forename: Mario P
authors.initials: MP
authors.lastname: Colombo
mesh_terms: D025601:Adenomatous Polyposis Coli Protein / Q000235:genetics / Q000378:metabolism; D000328:Adult; D000368:Aged; D000369:Aged, 80 and over; D000818:Animals; D001853:Bone Marrow / Q000187:drug effects / Q000378:metabolism* / Q000473:pathology; D051929:CD146 Antigen / Q000235:genetics / Q000378:metabolism; D049109:Cell Proliferation; D002478:Cells, Cultured; D005260:Female; D015870:Gene Expression; D006801:Humans; D007951:Leukemia, Myeloid / Q000139:chemically induced / Q000150:complications / Q000235:genetics* / Q000473:pathology; D008297:Male; D059630:Mesenchymal Stem Cells / Q000187:drug effects / Q000378:metabolism* / Q000473:pathology; D051379:Mice; D018345:Mice, Knockout; D008875:Middle Aged; D022423:Myeloid Cells / Q000187:drug effects / Q000378:metabolism* / Q000473:pathology; D015676:Osteonectin / Q000172:deficiency / Q000235:genetics* / Q000378:metabolism; D055728:Primary Myelofibrosis / Q000139:chemically induced / Q000150:complications / Q000235:genetics* / Q000473:pathology; D013926:Thrombopoietin / Q000009:adverse effects
chemical_list: D025601:Adenomatous Polyposis Coli Protein; D051929:CD146 Antigen; D015676:Osteonectin; D013926:Thrombopoietin