Crucial factors of the inflammatory microenvironment (IL-1β/ TNF-α/TIMP-1) promote the maintenance of the malignant hemopoietic clone of myelofibrosis: an in vitro study
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Daria Sollazzo1,*, Dorian Forte1,*, Nicola Polverelli1, Marco Romano1, Margherita Perricone1, Lara Rossi1, Emanuela Ottaviani1, Simona Luatti1, Giovanni Martinelli1, Nicola Vianelli1, Michele Cavo1, Francesca Palandri1,*, Lucia Catani1,*
1Department of Experimental, Diagnostic and Specialty Medicine, Institute of Hematology “L. e A. Seràgnoli”, University of Bologna, Bologna, Italy
*These authors contributed equally to this work
Lucia Catani, email: email@example.com
Keywords: circulating CD34+ cells, myelofibrosis, inflammatory microenvironment, migration, survival
Received: November 12, 2015 Accepted: May 20, 2016 Published: June 11, 2016
Along with molecular abnormalities (mutations in JAK2, Calreticulin (CALR) and MPL genes), chronic inflammation is the major hallmark of Myelofibrosis (MF). Here, we investigated the in vitro effects of crucial factors of the inflammatory microenvironment (Interleukin (IL)-1β, Tumor Necrosis Factor (TNF)-α, Tissue Inhibitor of Metalloproteinases (TIMP)-1 and ATP) on the functional behaviour of MF-derived circulating CD34+ cells.
We found that, regardless mutation status, IL-1β or TNF-α increases the survival of MF-derived CD34+ cells. In addition, along with stimulation of cell cycle progression to the S-phase, IL-1β or TNF-α ± TIMP-1 significantly stimulate(s) the in vitro clonogenic ability of CD34+ cells from JAK2V617 mutated patients. Whereas in the JAK2V617F mutated group, the addition of IL-1β or TNF-α + TIMP-1 decreased the erythroid compartment of the CALR mutated patients. Megakaryocyte progenitors were stimulated by IL-1β (JAK2V617F mutated patients only) and inhibited by TNF-α. IL-1β + TNF-α + C-X-C motif chemokine 12 (CXCL12) ± TIMP-1 highly stimulates the in vitro migration of MF-derived CD34+ cells. Interestingly, after migration toward IL-1β + TNF-α + CXCL12 ± TIMP-1, CD34+ cells from JAK2V617F mutated patients show increased clonogenic ability.
Here we demonstrate that the interplay of these inflammatory factors promotes and selects the circulating MF-derived CD34+ cells with higher proliferative activity, clonogenic potential and migration ability. Targeting these micro-environmental interactions may be a clinically relevant approach.
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