Constitutive NF-κB activation in AML: Causes and treatment strategies.
For more than a decade, it has been known that NF-κB is constitutively activated in a majority of acute myeloid leukemia (AML) patients which contributes to the resistance to apoptosis. Inhibition of NF-κB has been shown to induce apoptosis in AML cells, but the clinical effectiveness of NF-κB inhibitors has been inadequate. In recent years, possible causes underlying this continuous NF-κB activity have been elucidated. It has been shown that chromosomal translocations or mutations leading to development of leukemia drive the increase in NF-κB activity. Furthermore, autocrine/paracrine cytokine signaling and increased expression of NF-κB signaling components play an important role in the continuous NF-κB activation. Moreover, high proteasome activity, which positively regulates NF-κB activity, is often observed in AML patients. In the present study, we described these underlying molecular mechanisms leading to constitutive NF-κB activity and discussed the novel treatment strategies based on the inhibition of NF-κB activation.
Department of Experimental Hematology, University Medical Center Groningen, Cancer Research Center Groningen, University of Groningen, Hanzeplein 1, 9713 GZ, Groningen, The Netherlands.
Matthieu Cornelis Johannes
MC
Bosman
Department of Experimental Hematology, University Medical Center Groningen, Cancer Research Center Groningen, University of Groningen, Hanzeplein 1, 9713 GZ, Groningen, The Netherlands.
Jan Jacob
JJ
Schuringa
Department of Experimental Hematology, University Medical Center Groningen, Cancer Research Center Groningen, University of Groningen, Hanzeplein 1, 9713 GZ, Groningen, The Netherlands. Electronic address: e.vellenga@umcg.nl.
Edo
E
Vellenga
D017209:Apoptosis; D006410:Hematopoiesis; D006801:Humans; D015470:Leukemia, Myeloid, Acute / Q000188:drug therapy* / Q000235:genetics / Q000473:pathology; D058990:Molecular Targeted Therapy; D009154:Mutation; D016328:NF-kappa B / Q000037:antagonists & inhibitors / Q000502:physiology*; D015398:Signal Transduction; D014178:Translocation, Genetic
D016328:NF-kappa B
AML; Apoptosis; NF-κB; Survival