Journal
ONCOTARGET
Volume 7, Issue 28, Pages 43974-43988Publisher
IMPACT JOURNALS LLC
DOI: 10.18632/oncotarget.9949
Keywords
circulating CD34(+) cells; myelofibrosis; inflammatory microenvironment; migration; survival
Categories
Funding
- Associazione Italiana contro le Leucemie-Bologna section (BolognAIL)
- University of Bologna (RFO)
- European Union [306242-NGS-PTL]
- Progetto Regione-Universita
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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)-1 beta, Tumor Necrosis Factor (TNF)-alpha, 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-1 beta or TNF-alpha increases the survival of MF-derived CD34(+) cells. In addition, along with stimulation of cell cycle progression to the S-phase, IL-1 beta or TNF-alpha +/- TIMP-1 significantly stimulate(s) the in vitro clonogenic ability of CD34(+) cells from JAK2(V617) mutated patients. Whereas in the JAK2(V617F) mutated group, the addition of IL-1 beta or TNF-alpha +/- TIMP-1 decreased the erythroid compartment of the CALR mutated patients. Megakaryocyte progenitors were stimulated by IL-1 beta (JAK2(V617F) mutated patients only) and inhibited by TNF-alpha. IL-1 beta + TNF-alpha + 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-1 beta + TNF-alpha + CXCL12 +/- TIMP-1, CD34(+) cells from JAK2(V617F) 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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