bay-11-7082 and Leukemia--Myeloid--Acute

We previously reported that autocrine TNF-α (TNF) is responsible for JNK pathway activation in a subset of acute myeloid leukemia (AML) patient samples, providing a survival/proliferation signaling parallel to NF-κB in AML stem cells (LSCs). In this study, we report that most TNF-expressing AML cells (LCs) also express another pro-inflammatory cytokine, IL1β, which acts in a parallel manner. TNF was produced primarily by LSCs and leukemic progenitors (LPs), whereas IL1β was mainly produced by partially differentiated leukemic blasts (LBs). IL1β also stimulates an NF-κB-independent pro-survival and proliferation signal through activation of the JNK pathway. We determined that co-inhibition of signaling stimulated by both TNF and IL1β synergizes with NF-κB inhibition in eliminating LSCs both ex vivo and in vivo. Our studies show that such treatments are most effective in M4/5 subtypes of AML.

Topics: Animals; Antineoplastic Combined Chemotherapy Protocols; Cell Line, Tumor; Dose-Response Relationship, Drug; Etanercept; Humans; Interleukin 1 Receptor Antagonist Protein; Interleukin-1beta; Leukemia, Myeloid, Acute; Mice, Inbred C57BL; Mice, Knockout; Neoplastic Stem Cells; NF-kappa B; Nitriles; Receptors, Interleukin-1 Type I; Receptors, Tumor Necrosis Factor, Type I; Receptors, Tumor Necrosis Factor, Type II; Signal Transduction; Sulfones; Time Factors; Transfection; Tumor Cells, Cultured; Tumor Necrosis Factor-alpha