title: Osteogenic Potential of Mesenchymal Stromal Cells Contributes to Primary Myelofibrosis.
abstract: Primary myelofibrosis is a myeloproliferative neoplasm that is a precursor to myeloid leukemia. Dysmegakaryopoiesis and extramedullary hematopoiesis characterize primary myelofibrosis, which is also associated with bone marrow stromal alterations marked by fibrosis, neoangiogenesis, and osteomyelosclerosis. In particular, contributions to primary myelofibrosis from mesenchymal stromal cells (MSC) have been suggested by mouse studies, but evidence in humans remains lacking. In this study, we show that bone marrow MSCs from primary myelofibrosis patients exhibit unique molecular and functional abnormalities distinct from other myeloproliferative neoplasms and these abnormalities are maintained stably ex vivo in the absence of leukemic cells. Primary myelofibrosis-MSC overexpressed heparin-binding cytokines, including proinflammatory TGFβ1 and osteogenic BMP-2, as well as glycosaminoglycans such as heparan sulfate and chondroitin sulfate. Transcriptome and functional analyses revealed alterations in MSC differentiation characterized by an increased osteogenic potential and a TGFβ1 signaling signature. Accordingly, phospho-Smad2 levels were intrinsically increased in primary myelofibrosis-MSC along with enhanced expression of the master bone regulator RUNX2, while inhibition of the endogenous TGFβ1 receptor TGFβR1 impaired osteogenic differentiation in these MSCs. Taken together, our results define the source of a critical osteogenic function in primary myelofibrosis that supports its pathophysiology, suggesting that combined targeting of both the hematopoietic and stromal cell compartments in primary myelofibrosis patients may heighten therapeutic efficacy.
authors.affiliation: Inserm UMR-S1197, Paul Brousse Hospital, Villejuif, France. SFR89, Paris-Sud University, Villejuif, France. Department of Clinical Biology, Military Medical Centre Percy, Clamart, France. FIM, French Intergroup on Myeloproliferative neoplasms.
authors.forename: Christophe
authors.initials: C
authors.lastname: Martinaud
authors.affiliation: Inserm UMR-S1197, Paul Brousse Hospital, Villejuif, France. SFR89, Paris-Sud University, Villejuif, France.
authors.forename: Christophe
authors.initials: C
authors.lastname: Desterke
authors.affiliation: Department of Hematology, Military Medical Centre Percy, Clamart, France.
authors.forename: Johanna
authors.initials: J
authors.lastname: Konopacki
authors.affiliation: Center for Research and Innovation of MPN-CRIMM, Azienda Ospedaliera Universitaria Careggi, Department of Experimental and Clinical Medicine and DENOTHE Centre, University of Firenze, Firenze, Italia.
authors.forename: Lisa
authors.initials: L
authors.lastname: Pieri
authors.affiliation: Inserm UMR-S1197, Paul Brousse Hospital, Villejuif, France. SFR89, Paris-Sud University, Villejuif, France.
authors.forename: Frédéric
authors.initials: F
authors.lastname: Torossian
authors.affiliation: Institut Pasteur, Immunology Department, Lymphopoiesis Unit Paris, France. Université Paris-Diderot, Sorbonne Paris Cité, Cellule Pasteur, Paris, France. Inserm U668, Paris, France.
authors.forename: Rachel
authors.initials: R
authors.lastname: Golub
authors.affiliation: Institut Pasteur, Immunology Department, Lymphopoiesis Unit Paris, France.
authors.forename: Sandrine
authors.initials: S
authors.lastname: Schmutz
authors.affiliation: Inserm UMR-S1197, Paul Brousse Hospital, Villejuif, France. SFR89, Paris-Sud University, Villejuif, France.
authors.forename: Adrienne
authors.initials: A
authors.lastname: Anginot
authors.affiliation: Inserm UMR-S1197, Paul Brousse Hospital, Villejuif, France. SFR89, Paris-Sud University, Villejuif, France.
authors.forename: Bernadette
authors.initials: B
authors.lastname: Guerton
authors.affiliation: Université de Nice Sophia Antipolis, CNRS, iBV, UMR7277, Nice, France.
authors.forename: Nathalie
authors.initials: N
authors.lastname: Rochet
authors.affiliation: Université Paris Est, CRRET, UPEC, EAC 7149, Créteil, France.
authors.forename: Patricia
authors.initials: P
authors.lastname: Albanese
authors.affiliation: Université Paris Est, CRRET, UPEC, EAC 7149, Créteil, France.
authors.forename: Emilie
authors.initials: E
authors.lastname: Henault
authors.affiliation: Etablissement Français du Sang, Fort-de-France, Martinique.
authors.forename: Olivier
authors.initials: O
authors.lastname: Pierre-Louis
authors.affiliation: Department of Clinical Biology, Military Medical Centre Percy, Clamart, France.
authors.forename: Jean-Baptiste
authors.initials: JB
authors.lastname: Souraud
authors.affiliation: Department of Hematology, Military Medical Centre Percy, Clamart, France.
authors.forename: Thierry
authors.initials: T
authors.lastname: de Revel
authors.affiliation: Department of Hematology, CH Lens, France.
authors.forename: Brigitte
authors.initials: B
authors.lastname: Dupriez
authors.affiliation: Department of Hematology, CHU Brest, France.
authors.forename: Jean-Christophe
authors.initials: JC
authors.lastname: Ianotto
authors.affiliation: Inserm U785, Villejuif, France. AP-HP Hôpital Paul Brousse, Centre Hépato-Biliaire, Villejuif, France.
authors.forename: Marie-Françoise
authors.initials: MF
authors.lastname: Bourgeade
authors.affiliation: Center for Research and Innovation of MPN-CRIMM, Azienda Ospedaliera Universitaria Careggi, Department of Experimental and Clinical Medicine and DENOTHE Centre, University of Firenze, Firenze, Italia.
authors.forename: Alessandro M
authors.initials: AM
authors.lastname: Vannucchi
authors.affiliation: Inserm UMR-S1197, Paul Brousse Hospital, Villejuif, France. French Military Blood Transfusion Center, Clamart, France and Biomedical Research Institute of Armies (IRBA), Brétigny sur Orge, France.
authors.forename: Jean-Jacques
authors.initials: JJ
authors.lastname: Lataillade
authors.affiliation: Inserm UMR-S1197, Paul Brousse Hospital, Villejuif, France. SFR89, Paris-Sud University, Villejuif, France. FIM, French Intergroup on Myeloproliferative neoplasms. caroline.le-bousse-kerdiles@inserm.fr.
authors.forename: Marie-Caroline
authors.initials: MC
authors.lastname: Le Bousse-Kerdilès
mesh_terms: D000328:Adult; D000368:Aged; D000369:Aged, 80 and over; D000818:Animals; D002454:Cell Differentiation / Q000502:physiology*; D002478:Cells, Cultured; D005260:Female; D064593:Heterografts; D006801:Humans; D008297:Male; D059630:Mesenchymal Stem Cells / Q000473:pathology*; D051379:Mice; D008819:Mice, Nude; D008875:Middle Aged; D009999:Ossification, Heterotopic / Q000503:physiopathology*; D016133:Polymerase Chain Reaction; D055728:Primary Myelofibrosis / Q000503:physiopathology*