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Critical Reviews™ in Oncogenesis

ISSN Print: 0893-9675
ISSN Online: 2162-6448

Critical Reviews™ in Oncogenesis

DOI: 10.1615/CritRevOncog.v15.i1-2.10
pages 1-41

Nuclear Factor-κB Signaling: A Contributor in Leukemogenesis and a Target for Pharmacological Intervention in Human Acute Myelogenous Leukemia

Hakon Reikvam
Division for Hematology, Institute of Medicine, University of Bergen, Bergen, Norway
Astrid Marta Olsnes
Division for Hematology, Institute of Medicine, University of Bergen, and Department of Medicine, Haukeland University Hospital, Bergen, Norway
Bjorn Tore Gjertsen
Division for Hematology, Institute of Medicine, University of Bergen, and Department of Medicine, Haukeland University Hospital, Bergen, Norway
Elisabeth Ersvar
Division for Hematology, Institute of Medicine, University of Bergen, Bergen, Norway
Oystein Bruserud
Division for Hematology, Institute of Medicine, University of Bergen; and Department of Medicine, Haukeland University Hospital, Bergen, Norway

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-κB (NF-κB) transcription factor family is one of the therapeutic strategies that are considered in AML. NF-κB is an important regulator of several biological processes that are involved in leukemogenesis, including proliferation, differentiation, autophagy, and apoptosis. Constitutive NF-κB activation has been detected in AML cells and NF-κB inhibition is therefore a possible therapeutic strategy in AML. Multiple pharmacological agents have shown inhibitory effects against NF-κB 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-κB inhibition, but this therapeutic approach should possibly be combined with other therapeutic agents to achieve a combined effect both on NF-κB transcriptional activity, tumor suppressor-induced signaling, and stress-induced pathways. The clinical documentation with regard to the efficiency and safety of NF-κB inhibition is still limited, but experimental evidence strongly suggests that NF-κB inhibition should be further investigated in human AML.