Stromal SPARC contributes to the detrimental fibrotic changes associated with myeloproliferation whereas its deficiency favors myeloid cell expansion

• Published in: Blood Vol. 120; no. 17; pp. 3541 - 3554
• Main Authors: Tripodo, Claudio, Sangaletti, Sabina, Guarnotta, Carla, Piccaluga, Pier P., Cacciatore, Matilde, Giuliano, Michela, Franco, Giovanni, Chiodoni, Claudia, Sciandra, Marika, Miotti, Silvia, Calvaruso, Giuseppe, Carè, Alessandra, Florena, Ada M., Scotlandi, Katia, Orazi, Attilio, Pileri, Stefano A., Colombo, Mario P.
• Format: Journal Article
• Language: English
• Published: Washington, DC Elsevier Inc 25.10.2012; Americain Society of Hematology
• Subjects: Adenomatous Polyposis Coli Protein - genetics; Adenomatous Polyposis Coli Protein - metabolism; Adult; Aged; Aged, 80 and over; Animals; Biological and medical sciences; Bone Marrow - drug effects; Bone Marrow - metabolism; Bone Marrow - pathology; CD146 Antigen - genetics; CD146 Antigen - metabolism; Cell Proliferation; Cells, Cultured; Female; Gene Expression; Hematologic and hematopoietic diseases; Humans; Leukemia, Myeloid - chemically induced; Leukemia, Myeloid - complications; Leukemia, Myeloid - genetics; Leukemia, Myeloid - pathology; Male; Medical sciences; Mesenchymal Stem Cells - drug effects; Mesenchymal Stem Cells - metabolism; Mesenchymal Stem Cells - pathology; Mice; Mice, Knockout; Middle Aged; Myeloid Cells - drug effects; Myeloid Cells - metabolism; Myeloid Cells - pathology; Osteonectin - deficiency; Osteonectin - genetics; Osteonectin - metabolism; Primary Myelofibrosis - chemically induced; Primary Myelofibrosis - complications; Primary Myelofibrosis - genetics; Primary Myelofibrosis - pathology; Thrombopoietin - adverse effects; Hematology; Deficiency; Fibrosis; Osteonectin; Stroma; Myeloid cell; Expansion
• ISSN: 0006-4971; 1528-0020; 1528-0020
• DOI: 10.1182/blood-2011-12-398537

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 Apcmin 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.