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-κB pathway activation has been reported in different types of AML; however, the mechanism of NF-κB activation and its importance in leukemia progression are poorly understood. Here, we analyzed myeloid leukemia mouse models to assess NF-κB activity in AML LICs. We found that LICs, but not normal hematopoietic stem cells or non-LIC fractions within leukemia cells, exhibited constitutive NF-κB activity. This activity was maintained through autocrine TNF-α secretion, which formed an NF-κB/TNF-α positive feedback loop. LICs had increased levels of active proteasome machinery, which promoted the degradation of IκBα and further supported NF-κB activity. Pharmacological inhibition of the proteasome complex markedly suppressed leukemia progression in vivo. Conversely, enhanced activation of NF-κB signaling expanded LIC frequency within leukemia cell populations. We also demonstrated a strong correlation between NF-κB activity and TNF-α secretion in human AML samples. Our findings indicate that NF-κB/TNF-α signaling in LICs contributes to leukemia progression and provide a widely applicable approach for targeting LICs.

Complications of delirium and dementia increase mortality; however, it is difficult to diagnose delirium accurately, especially among dementia patients. The bispectral electroencephalography (BSEEG) score can detect delirium and predict mortality in elderly patients. We aimed to develop an efficient and reliable BSEEG device for high-throughput screening. We also hypothesized that BSEEG score can predict mortality among dementia patients. A prospective cohort study was conducted between January 2016 to December 2018 to measure BSEEG from elderly patients and correlate with outcomes. A total of 502 elderly (55 years old or older) patients with and without dementia were enrolled. For a replication of the utility of BSEEG, mortalities between BSEEG-positive and BSEEG-negative group were compared. In addition, patients with and without dementia status was added to examine the utility of BSEEG among dementia patients. The mortality within 180 days in the BSEEG-positive group was higher than that of the BSEEG-negative group in both the replication and the total cohorts. Mortality of those in the BSEEG-positive group showed a dose-dependent increase in both cohorts. When the dementia patients showed BSEEG positive, their mortality was significantly higher than those with dementia but who were BSEEG-negative. Mortality within 30 days in the BSEEG-positive group was significantly higher than that of the BSEEG-negative group. The utility of the BSEEG to predict mortality among large sample of 502 elderly patients was shown. The BSEEG score can predict mortality among elderly patients in general, and even among dementia patients, as soon as 30 days.

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