Positive feedback between NF-κB and TNF-α promotes leukemia-initiating cell capacity

Abstract

Acute myeloid leukemia (AML) is a heterogeneous hematologic malignancy that originates from leukemia-initiating cells (LICs). The identification of common mechanisms underlying LIC development will be important in establishing broadly effective therapeutics for AML. Constitutive NF-κB pathway activation has been reported in different types of AML; however, the mechanism of NF-κB activation and its importance in leukemia progression are poorly understood. Here, we analyzed myeloid leukemia mouse models to assess NF-κB activity in AML LICs. We found that LICs, but not normal hematopoietic stem cells or non-LIC fractions within leukemia cells, exhibited constitutive NF-κB activity. This activity was maintained through autocrine TNF-α secretion, which formed an NF-κB/TNF-α positive feedback loop. LICs had increased levels of active proteasome machinery, which promoted the degradation of IκBα and further supported NF-κB activity. Pharmacological inhibition of the proteasome complex markedly suppressed leukemia progression in vivo. Conversely, enhanced activation of NF-κB signaling expanded LIC frequency within leukemia cell populations. We also demonstrated a strong correlation between NF-κB activity and TNF-α secretion in human AML samples. Our findings indicate that NF-κB/TNF-α signaling in LICs contributes to leukemia progression and provide a widely applicable approach for targeting LICs.

Enhancement of active MMP release and invasive activity of lymph node metastatic tongue cancer cells by elevated signaling via the TNF-α-TNFR1-NF-κB pathway and a possible involvement of angiopoietin-like 4 in lung metastasis

“…4) in relation to elevated NF-κB activation (Fig. 3B) agrees with that NF-κB activation leading to TNF-α production in tumor cells (31,32). NF-κB is a key regulator of MMP-2 and MMP-9 expression (33,34), even in SAS cells (35) Figure 5.…”

“…This may be an underlying mechanism by which GSAS/N3 and GSAS/N5 cells exert high invasive and metastatic activities. Such a positive feedback between NF-κB and TNF-α was reported in leukemia-initiating cells and contributes to leukemia progression (32). The present study suggests that this mechanism is present in the oral cancer cells and associated with enhanced secretion of active MMPs, augmenting invasion and probably metastasis of the malignant cells.…”

“…These results indicated elevation of the signaling pathway to NF-κB and resultant increase of NF-κB activation in the highly metastatic oral SCC cells. NF-κB activation leads to TNF-α production in cancer cells (31,32), thus, TNF-α secretion from the cancer cells was measured. In agreement with increased TNF-α mRNA expression ( Fig.…”

Therapeutically targeting SELF‐reinforcing leukemic niches in acute myeloid leukemia: A worthy endeavor?

“…It is well-known that MSCs actively participate in the "angiogenic switch" not only by releasing various angiogenic factors [62], but also by recruiting circulating vascular progenitor cells [63]. MSCs may inhibit adaptive and innate immunity by releasing immunosuppressive cytokines and effectors including tumor necrosis a (TNF-a) and interferon-g (IFN-g) either directly or under the influence of leukemic cells [64][65][66][67]. In addition, under the influence of Axl-expressing leukemic cells, BM derived MSCs are induced to express and produce the Axl ligand, i.e.…”

“…IL6, too, might be a suitable and up to date target since high IL-6 levels have been associated with a poor clinical outcome and refractory disease [66] and humanized monoclonal antibodies against the IL-6 receptor are nowadays available. Recently, it has been observed that TNF-a released from stromal cells might be minimal, but this cytokine along with a high proteasome activity is critical for maintaining the constitutive activation of nuclear factor Kb (NFkB) in LICs but not in HSCs and non-LIC fractions of AML cells [67]. Thus, combining the inhibition of NFkB/TNF-a signaling with conventional chemotherapy might be a beneficial treatment strategy.…”