Abstract
Despite high basal NF-kappaB activity in acute myeloid leukemia (AML) cells, inhibiting NF-kappaB in these cells has little or no effect on inducing apoptosis. We previously showed that heme oxygenase-1 (HO-1) underlies this resistance of AML to tumor necrosis factor-induced apoptosis. Here, we describe a mechanism by which HO-1 is a silent antiapoptotic factor only revealed when NF-kappaB is inhibited, thus providing a secondary antiapoptotic mechanism to ensure AML cell survival and chemoresistance. We show that inhibition of NF-kappaB increased HO-1 expression in primary AML cells compared with that of nonmalignant cells. In addition, we observed this suppressed HO-1 level in AML cells compared with CD34(+) nonmalignant control cells. Using chromatin immunoprecipitation assay and small interfering RNA knockdown, we showed that the NF-kappaB subunits p50 and p65 control this suppression of HO-1 in AML cells. Finally, we showed that inhibition of HO-1 and NF-kappaB in combination significantly induced apoptosis in AML cells but not in noncancerous control cells. Thus, NF-kappaB inhibition combined with HO-1 inhibition potentially provides a novel therapeutic approach to treat chemotherapy-resistant forms of AML.
Highlights
Acute myeloid leukemia (AML) is a heterogeneous clonal disorder of hematopoietic stem cells (HSC), characterized by proliferation and differentiation of abnormal cells, causing accumulation of immature myeloid cells in bone marrow and blood
To understand the function of NF-κB in AML cells, we examined the nuclear profile of NF-κB subunits in human AML cells compared with nonmalignant control cells
We showed that AML has low heme oxygenase-1 (HO-1) expression when compared with nonmalignant control cells
Summary
Acute myeloid leukemia (AML) is a heterogeneous clonal disorder of hematopoietic stem cells (HSC), characterized by proliferation and differentiation of abnormal cells, causing accumulation of immature myeloid cells in bone marrow and blood. NF-κB is a family of transcription factors that share homology to the retroviral oncoprotein v-Rel. The five members of the mammalian NF-κB family consist of the class I proteins NF-κB1 (p105→p50) and NF-κB2 (p100→p52) and class II proteins RelA (p65), RelB, and c-Rel. Inhibitors of NF-κB have emerged as potential therapies against AML [2]. Inhibitors of NF-κB have emerged as potential therapies against AML [2] This is because AML blasts have constitutive NF-κB activation [3]. Such abnormal levels of constitutively activated NF-κB
Sign-in/Register to view highlights & summary 
Submitted Version (
Free)
Published Version
Talk to us
Join us for a 30 min session where you can share your feedback and ask us any queries you have
Schedule a call