NF-κB pathways in hematological malignancies

Abstract

The nuclear factor κB or NF-κB transcription factor family plays a key role in several cellular functions, i.e. inflammation, apoptosis, cell survival, proliferation, angiogenesis, and innate and acquired immunity. The constitutive activation of NF-κB is typical of most malignancies and plays a major role in tumorigenesis. In this review, we describe NF-κB and its two pathways: the canonical pathway (RelA/p50) and the non-canonical pathway (RelB/p50 or RelB/p52). We then consider the role of the NF-κB subunits in the development and functional activity of B cells, T cells, macrophages and dendritic cells, which are the targets of hematological malignancies. The relevance of the two pathways is described in normal B and T cells and in hematological malignancies, acute and chronic leukemias (ALL, AML, CLL, CML), B lymphomas (DLBCLs, Hodgkin's lymphoma), T lymphomas (ATLL, ALCL) and multiple myeloma. We describe the interaction of NF-κB with the apoptotic pathways induced by TRAIL and the transcription factor p53. Finally, we discuss therapeutic anti-tumoral approaches as mono-therapies or combination therapies aimed to block NF-κB activity and to induce apoptosis (PARAs and Nutlin-3).

Fig. 1

The canonical and non-canonical pathways of NF-κB and their interaction with the apoptotic pathways. The canonical and non-canonical NF-κB signaling pathways are represented in the center and to the right of the figure. The canonical pathway is activated through the TNF receptors’ family, TLR4 and the antigen receptors BCR and TCR, while the non-canonical pathway is activated through a limited number of receptors, such as BAFF-R, CD40, RANK, CD30, and LTβ-R. The apoptotic pathways are summarized to the left of the figure in the extrinsic pathway (mediated by TRAIL) and the intrinsic pathway (mediated by p53). Arrows indicate activating steps, and bars indicate inhibitory steps. Numbers in circles indicate the steps of the apoptotic pathways inhibited by molecules that are induced by NF-κB activation (c-FLIP, Bcl-2 family’s molecules, IAPs). This is the case of ① procaspase 8 and 10, whose activation is inhibited by cFLIP, ② the pro-apoptotic molecules Bak/Bax inhibited by the pro-survival Bcl2, Bcl-X_L, Mcl-1, ③ the effector caspases 3, 6, 7 targeted by the inhibitors of apoptosis (IAPs) family proteins, ④ the transcription factor p53 inhibited directly or indirectly by NF-κB