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Cancer Res. 2015 Nov 15;75(22):4753-65. doi: 10.1158/0008-5472.CAN-14-3696. Epub 2015 Sep 24.

Osteogenic Potential of Mesenchymal Stromal Cells Contributes to Primary Myelofibrosis.

Author information

1
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.
2
Inserm UMR-S1197, Paul Brousse Hospital, Villejuif, France. SFR89, Paris-Sud University, Villejuif, France.
3
Department of Hematology, Military Medical Centre Percy, Clamart, France.
4
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.
5
Institut Pasteur, Immunology Department, Lymphopoiesis Unit Paris, France. Université Paris-Diderot, Sorbonne Paris Cité, Cellule Pasteur, Paris, France. Inserm U668, Paris, France.
6
Institut Pasteur, Immunology Department, Lymphopoiesis Unit Paris, France.
7
Université de Nice Sophia Antipolis, CNRS, iBV, UMR7277, Nice, France.
8
Université Paris Est, CRRET, UPEC, EAC 7149, Créteil, France.
9
Etablissement Français du Sang, Fort-de-France, Martinique.
10
Department of Clinical Biology, Military Medical Centre Percy, Clamart, France.
11
Department of Hematology, CH Lens, France.
12
Department of Hematology, CHU Brest, France.
13
Inserm U785, Villejuif, France. AP-HP Hôpital Paul Brousse, Centre Hépato-Biliaire, Villejuif, France.
14
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.
15
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.

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.

PMID:
26404004
DOI:
10.1158/0008-5472.CAN-14-3696
[Indexed for MEDLINE]
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