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

Abstract

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.

Autocrine Tnf signaling favors malignant cells in myelofibrosis in a Tnfr2-dependent fashion

“…Consistent with their modest effects in MF patients, etanercept and infliximab failed to reduce MPN disease in mice with JAK2 V617F MPN (Supplemental Figure 2 ). These results are at odds with the attenuation of MPN in a previous study using TNF deficient mice [ 2 ] and suggest that additional, unintended effects, of pan-TNF antagonists may neutralize differences in TNF responses between MF and normal cells [ 2 , 47 ]. Several studies have implicated TNF as a negative regulator of HSCs [ 48 – 50 ].…”

“…It is also possible that the over-expression of JAK2 V617F induced by the transduction/transplantation model may have amplified the effect in the mouse cells relative to the human samples. We selected this model because plasma TNF concentrations are elevated over controls to a similar degree as in MF (~10–15-fold) [ 26 , 47 ].…”

Cold shock proteins: from cellular mechanisms to pathophysiology and disease

“…The modulation of tumor necrosis factor receptor signaling by extracellular cold shock proteins is relevant to a number of diseases, including preeclampsia, diabetic nephropathy, systemic lupus erythematosus, liver fibrosis, and infectious diseases where TNF plays a central role in disease pathology [ 183 ]. Additionally, TNF promotes expansion of JAK2V617F positive cells in myeloproliferative neoplasms [ 184 ]. Extracellular cold shock proteins are also topics of interest, as is their potential role in fetal-maternal communication during implantation.…”

Tumor necrosis factor alpha is a promising circulating biomarker for the development of obstructive sleep apnea syndrome: a meta-analysis

“…Tumor necrosis factor alpha (TNF-alpha) is a key modulator of systematic inflammation [8–10], and TNF inhibition has proven to ameliorate the progression of OSAS [11]. Moreover, some researchers have observed a significant high level of circulating TNF-alpha in OSAS patients vis-à-vis healthy individuals [12–18], whereas others did not [19, 20].…”