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. Cancer Res; 75(22); 4753-65. ©2015 AACR.

Osteogenic Potential of Mesenchymal Stromal Cells Contributes to Primary Myelofibrosis / Martinaud, Christophe; Desterke, Christophe; Konopacki, Johanna; Pieri, Lisa; Torossian, Frédéric; Golub, Rachel; Schmutz, Sandrine; Anginot, Adrienne; Guerton, Bernadette; Rochet, Nathalie; Albanese, Patricia; Henault, Emilie; Pierre-Louis, Olivier; Souraud, Jean-Baptiste; de Revel, Thierry; Dupriez, Brigitte; Ianotto, Jean-Christophe; Bourgeade, Marie-Françoise; Vannucchi, Alessandro M; Lataillade, Jean-Jacques; Le Bousse-Kerdilès, Marie-Caroline. - In: CANCER RESEARCH. - ISSN 0008-5472. - STAMPA. - 75:(2015), pp. 4753-65-4765. [10.1158/0008-5472.CAN-14-3696]

Osteogenic Potential of Mesenchymal Stromal Cells Contributes to Primary Myelofibrosis

PIERI, LISA;VANNUCCHI, ALESSANDRO MARIA;
2015

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. Cancer Res; 75(22); 4753-65. ©2015 AACR.
2015
75
4753-65
4765
Goal 3: Good health and well-being for people
Martinaud, Christophe; Desterke, Christophe; Konopacki, Johanna; Pieri, Lisa; Torossian, Frédéric; Golub, Rachel; Schmutz, Sandrine; Anginot, Adrienne...espandi
File in questo prodotto:
Non ci sono file associati a questo prodotto.

I documenti in FLORE sono protetti da copyright e tutti i diritti sono riservati, salvo diversa indicazione.

Utilizza questo identificatore per citare o creare un link a questa risorsa: https://hdl.handle.net/2158/1012245
Citazioni
  • ???jsp.display-item.citation.pmc??? ND
  • Scopus 41
  • ???jsp.display-item.citation.isi??? 37
social impact