NF-κB as a potential therapeutic target in myelodysplastic syndromes and acute myeloid leukemia

The inactive NF-κB-inhibitor of NF-κB (IκB) complex is activated by stimuli including pro-inflammatory cytokines, mitogens, growth factors and stress-inducing agents. The release of NF-κB facilitates its translocation to the nucleus, where it promotes cell survival by initiating transcription of genes encoding stress-response enzymes, cell-adhesion molecules, pro-inflammatory cytokines and anti-apoptotic proteins. NF-κB and associated regulatory factors (IκB kinase subunits and bcl-3) are implicated in hematological and solid tumour malignancies. NF-κB appears to be involved in cell proliferation control, apoptosis control, angiogenesis promotion and possibly regulation of diffusion of metastases. There are several reports that inhibition of NF-κB as a therapeutic target may have a role in tumour cell death or growth inhibition.

We review data about inhibition of NF-κB in acute myeloid leukemia (AML) and myelodysplastic syndromes (MDS). We describe the molecular mechanisms underlying NF-κB deregulation in these haematological malignancies.

Constitutive activation of NF-κB in the nucleus has been reported in some varieties of MDS/AML. The in vitro and in vivo results of NF-κB inhibition in myeloid malignancies are highlighted.

NF-κB selective inhibitory drugs may be useful, either as single agents or associated with conventional chemotherapy.