TNF-α Regulates the Effects of Irradiation in the Mouse Bone Marrow Microenvironment

Abstract

BackgroundSecondary bone marrow (BM) myelodysplastic syndromes (MDS) are increasingly common, as a result of radio or chemotherapy administered to a majority of cancer patients. Patients with secondary MDS have increased BM cell apoptosis, which results in BM dysfunction (cytopenias), and an increased risk of developing fatal acute leukemias. In the present study we asked whether TNF-α, known to regulate cell apoptosis, could modulate the onset of secondary MDS.Principal FindingsWe show that TNF-α is induced by irradiation and regulates BM cells apoptosis in vitro and in vivo. In contrast to irradiated wild type (WT) mice, TNF-α deficient (TNF-α KO) mice or WT mice treated with a TNF-α-neutralizing antibody were partially protected from the apoptotic effects of irradiation. Next we established a 3-cycle irradiation protocol, in which mice were sub-lethally irradiated once monthly over a 3 month period. In this model, irradiated WT mice presented loss of microsatellite markers on BM cells, low white blood cell (WBC) counts, reduced megakaryocyte (MK) and platelet levels (thrombocytopenia) and macrocytic anemia, phenoypes that suggest the irradiation protocol resulted in BM dysfunction with clinical features of MDS. In contrast, TNF-α KO mice were protected from the irradiation effects: BM cell apoptosis following irradiation was significantly reduced, concomitant with sustained BM MK numbers and absence of other cytopenias. Moreover, irradiated WT mice with long term (≥5 months) BM dysfunction had increased BM angiogenesis, MMPs and VEGF and NFkB p65, suggestive of disease progression.ConclusionTaken together, our data shows that TNF-α induction following irradiation modulates BM cell apoptosis and is a crucial event in BM dysfunction, secondary MDS onset and progression.

Endothelial-specific inhibition of NF-κB enhances functional haematopoiesis

“…Following irradiation, control BMECs (CD45 − TER119 − VECAD + ) demonstrated a transient spike in NF-κB signalling followed by a decrease, and ultimately returning to homeostatic levels by day 28 (Fig. 4a), which is consistent with a reported increase in WBM TNFα expression immediately following radiation-induced myelosuppression42. Analysis of peripheral blood in Tie2::IκB-SS mice revealed that endothelial-specific NF-κB inhibition protected white blood cell, red blood cell and total platelet loss following irradiation, with a rapid return to pre-irradiation levels (Fig.…”

Why does the bone marrow fail in Fanconi anemia?

“…In fact, high levels of cytokines can be induced by cytotoxic agents. 89 Recent work from Matsui and colleagues has, for the first time, looked at cytokine production by bone marrow cells from patients with different inherited BMF syndromes. This work contradicts previous studies because no evidence for the overproduction of TNF-a or IFN-g by unstimulated Fanconi-deficient T cells could be found.…”

Bone marrow malignancies as paradigms of dysfunctional cell adhesion mechanisms

“…One is the loss of the retinoic acid receptor- [126] and the other is due to a retinoblastoma protein-dependent interaction between myeloid-derived cells and the microenvironment [127] . Recently, our own studies showed that increased TNF-α levels occurring in BM microenvironment after radiation contribute towards the onset and progression of secondary MDS in mice [163] . The latter report indicated that ECM turnover is altered in irradiated (pre-malignant) BM, and that this contributes towards the onset of hematological dysfunction.…”