Microenvironmental interleukin-6 suppresses toll-like receptor signaling in human leukemia cells through miR-17/19A

Abstract

Key Points• IL-6 from splenic stromal cells prevents CLL cells from responding strongly to TLR ligands.• IL-6-signaling inhibitors enhance TLR-mediated responses of CLL cells in vitro and in vivo.The regulation of toll-like receptor (TLR) signaling in a tumor microenvironment is poorly understood despite its importance in cancer biology. To address this problem, TLR7-responses of chronic lymphocytic leukemia (CLL) cells were studied in the presence and absence of a human stromal cell-line derived from a leukemic spleen. CLL cells alone produced high levels of tumor necrosis factor (TNF)-a and proliferated in response to TLR7-agonists. A signal transducer and activator of transcription 3 -activating stromal factor, identified as interleukin (IL)-6, was found to upregulate microRNA (miR)-17 and miR-19a, target TLR7 and TNFA messenger RNA, and induce a state of tolerance to TLR7-agonists in CLL cells. Overexpression of the miR-17-92 cluster tolerized CLL cells directly and miR-17 and miR-19a antagomiRs restored TLR7-signaling. Inhibition of IL-6 signaling with antibodies or small-molecule Janus kinase inhibitors reversed tolerization and increased TLR7-stimulated CLL cell numbers in vitro and in NOD-SCIDg c null mice. These results suggest IL-6 can act as tumor suppressor in CLL by inhibiting TLR-signaling. (Blood. 2015;126(6):766-778)

Activity of the Janus kinase inhibitor ruxolitinib in chronic lymphocytic leukemia: results of a phase II trial

“…2,3 Plasma levels of a number of chemokines and cytokines were changed by Ruxolitinib, including GCSF, which increased in all patients ( Figure 1D).…”

“…[2][3][4] We hypothesized that Ruxolitinib, a selective JAK1/2 inhibitor licensed for myelofibrosis, 5 might have unrecognized activity in CLL and designed a single center phase II trial to evaluate it in patients considered unfit for FCR on the basis of age and comorbidities. 6 The demonstrated safety of Ruxolitinib in myelofibrosis was felt to make it ethical to use as first-line therapy for elderly CLL patients.…”

“…Lower panel: miR-17 expression was measured at these times by quantitative real-time PCR as before. 3 (D) Plasma collected before each treatment cycle was analyzed by multiplex laser-bead technology (Eve Technologies, Calgary, AB). The summary graph indicates GCSF levels before treatment and the greatest change following treatment with Ruxolitinib.…”

High-content screening identifies kinase inhibitors that overcome venetoclax resistance in activated CLL cells

“…[16][17][18] To address the effect of venetoclax on cells in PCs, a previously characterized in vitro model was used where CLL cells from patient-derived blood are stimulated in serum-free conditions with IL2 to represent T-cell signaling and Toll-like receptor 7/8 (TLR-7/8) agonist resiquimod to provide NF-kB-activating signals ( Figure 1A). [12][13][14]19 Such stimulated CLL cells (called "2S" cells) increase in size, change their morphology from a round to elongated shape, and proliferate in clusters ( Figure 1A). 12,13 Venetoclax rapidly killed unstimulated CLL cells from most patients ( Figure 1B, top panel), whereas 2S-stimulated cells exhibited varying degrees of resistance to 10 nM venetoclax, a concentration that is considered to be on-target for BH3-mediated killing.…”

Differentially expressed miRNAs in hepatocellular carcinoma cells under hypoxic conditions are associated with transcription and phosphorylation

“…MicroRNAs (miRNAs) have also been demonstrated to be involved in the process of cellular adaptation to the hypoxic microenvironment (3). miRNAs are non-coding single-stranded RNAs of ~22 nucleotides that mediate sequence-dependent post-transcriptional negative regulation of gene expression, and are known to serve a function in fundamental processes including cell proliferation (4), metabolism (5) and cancer metastasis (6), in addition to canonical signaling pathways including Notch, mitogen-activated protein kinase (MAPK) (7) and the Toll-like receptor signaling pathways (7,8). The study of the biological significance and utility of miRNAs is an expanding field, and it is increasingly evident that miRNAs serve complex functions and diverse functions specific to individual miRNA sequence, cell type and tissue environment.…”