Nuclear factor-kappaB signaling: a contributor in leukemogenesis and a target for pharmacological intervention in human acute myelogenous leukemia

Abstract

Acute myeloid leukemia (AML) is an aggressive malignancy with only 40%-50% long-term survival even for younger patients who can receive the most aggressive therapy. For elderly patients who only receive palliative treatment, the median survival is only 2-3 months. Inhibition of the nuclear factor-kappaB (NF-kappaB) transcription factor family is one of the therapeutic strategies that are considered in AML. NF-kappaB is an important regulator of several biological processes that are involved in leukemogenesis, including proliferation, differentiation, autophagy, and apoptosis. Constitutive NF-kappaB activation has been detected in AML cells and NF-kappaB inhibition is therefore a possible therapeutic strategy in AML. Multiple pharmacological agents have shown inhibitory effects against NF-kappaB signaling pathways, including proteasome inhibitors as well as the more-specific agents that are directed against various steps of this signaling pathway. Recent studies strongly suggest that primary human AML cells (including AML stem cells) are susceptible to NF-kappaB inhibition, but this therapeutic approach should possibly be combined with other therapeutic agents to achieve a combined effect both on NF-kappaB transcriptional activity, tumor suppressor-induced signaling, and stress-induced pathways. The clinical documentation with regard to the efficiency and safety of NF-kappaB inhibition is still limited, but experimental evidence strongly suggests that NF-kappaB inhibition should be further investigated in human AML.