Positive feedback between NF-?B and TNF-? promotes leukemia-initiating cell capacity.

ABSTRACT: Acute myeloid leukemia (AML) is a heterogeneous hematologic malignancy that originates from leukemia-initiating cells (LICs). The identification of common mechanisms underlying LIC development will be important in establishing broadly effective therapeutics for AML. Constitutive NF-?B pathway activation has been reported in different types of AML; however, the mechanism of NF-?B activation and its importance in leukemia progression are poorly understood. Here, we analyzed myeloid leukemia mouse models to assess NF-?B activity in AML LICs. We found that LICs, but not normal hematopoietic stem cells or non-LIC fractions within leukemia cells, exhibited constitutive NF-?B activity. This activity was maintained through autocrine TNF-? secretion, which formed an NF-?B/TNF-? positive feedback loop. LICs had increased levels of active proteasome machinery, which promoted the degradation of I?B? and further supported NF-?B activity. Pharmacological inhibition of the proteasome complex markedly suppressed leukemia progression in vivo. Conversely, enhanced activation of NF-?B signaling expanded LIC frequency within leukemia cell populations. We also demonstrated a strong correlation between NF-?B activity and TNF-? secretion in human AML samples. Our findings indicate that NF-?B/TNF-? signaling in LICs contributes to leukemia progression and provide a widely applicable approach for targeting LICs.

SUBMITTER: Kagoya Y 

PROVIDER: S-EPMC3904603 | biostudies-literature | 2014 Feb

REPOSITORIES: biostudies-literature