Abstract
The overall survival of patients with acute myeloid leukemia (AML) has not been improved significantly over the last decade. Molecularly targeted agents hold promise to change the therapeutic landscape in AML. The nuclear factor kappa B (NF-κB) controls a plethora of biological process through switching on and off its long list of target genes. In AML, constitutive NF-κB has been detected in 40% of cases and its aberrant activity enable leukemia cells to evade apoptosis and stimulate proliferation. These facts suggest that NF-κB signaling pathway plays a fundamental role in the development of AML and it represents an attractive target for the intervention of AML. This review summarizes our current knowledge of NF-κB signaling transduction including canonical and non-canonical NF-κB pathways. Then we specifically highlight what factors contribute to the aberrant activation of NF-κB activity in AML, followed by an overview of 8 important clinical trials of the first FDA approved proteasome inhibitor, Bortezomib (Velcade), which is a NF-κB inhibitor too, in combination with other therapeutic agents in patients with AML. Finally, this review discusses the future directions of NF-κB inhibitor in treatment of AML, especially in targeting leukemia stem cells (LSCs).
Highlights
The nuclear factor kappa B (NF-κB) is a dimeric transcription factor which plays versatile crucial roles in a plethora of normal cellular functions by controlling a panoply of downstream genes [1,2,3,4]
Upon activation of NF-κB, an upstream IB kinase phosphorylates IκBs at the critical amino acid residues (Ser-32 and Ser-36 of IκBα; Ser-19 and Ser23 of IκBβ), which are subsequently ubiquitinated by β-transducin repeat-containing protein and degraded by the 26S proteasome, allowing freed NF-κB dimers to translocate to the nucleus and transactivate κBresponsive elements [3, 15,16,17]
There are 8 different classes of more than 700 NFκB inhibitors, only a few of them have advanced into clinical trials for treatment of acute myeloid leukemia (AML)
Summary
The nuclear factor kappa B (NF-κB) is a dimeric transcription factor which plays versatile crucial roles in a plethora of normal cellular functions by controlling a panoply of downstream genes [1,2,3,4]. These two pathways have different 1) activating stimuli, 2) IKK activating complexes, 3) DNA-binding heterodimers and 4) gene target [22]. Causes of such aberrant activity could be due to alterations of genes that encode NF-κB and/or its inhibitors that promote NF-κB activation; constitutive activation of IKKs that accelerate IκB phosphorylation following degradation; or exposure to inflammatory stimuli in the tumour microenvironment that constantly trigger the signaling pathway.
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