Prolonging microtubule dysruption enhances the immunogenicity of chronic lymphocytic leukaemia cells

Shaha, Suchinta; Tomić, Jelena; Shi, Yonghong; Pham, Theodore; Mero, Patricia; White, Dionne; He, Lin; Baryza, Jeremy; Wender, Paul A.; Booth, James W.; Spaner, David

doi:10.1111/j.1365-2249.2009.04003.x

Cited by 25 publications

(24 citation statements)

References 33 publications

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“…10,25 GlcNAc and uridine increased O-GlcNAcylated protein levels in CLL cells, as shown by immunoblotting with RL2 (Figure 3a, right panel), while TNF-α expression in response to 852A decreased (Figure 3a, compare the upper and lower dot-plots). When O-GlcNAc levels were decreased by X1 (Figure 3b, right panel), TNF-α expression increased following stimulation with 852A (Figure 3b, compare the upper and lower dot-plots).…”

Section: Resultsmentioning

confidence: 78%

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Aberrant O-GlcNAcylation characterizes chronic lymphocytic leukemia

et al. 2010

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O-linked N-Acetylglucosamine (O-GlcNAc) post-translational modifications originate from the activity of the hexosamine pathway, and are known to affect intracellular signaling processes. As aberrant responses to microenvironmental signals are a feature of chronic lymphocytic leukemia (CLL), O-GlcNAcylated protein levels were measured in primary CLL cells. In contrast to normal circulating and tonsillar B cells, CLL cells expressed high levels of O-GlcNAcylated proteins, including p53, c-myc and Akt. O-GlcNAcylation in CLL cells increased following activation with cytokines and through toll-like receptors (TLRs), or after loading with hexosamine pathway substrates. However, high baseline O-GlcNAc levels were associated with impaired signaling responses to TLR agonists, chemotherapeutic agents, B cell receptor crosslinking and mitogens. Indolent and aggressive clinical behavior of CLL cells were found to correlate with higher and lower O-GlcNAc levels, respectively. These findings suggest that intracellular O-GlcNAcylation is associated with the pathogenesis of CLL, which could potentially have therapeutic implications.

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Section: Resultsmentioning

confidence: 78%

“…25 Phosphorylation of JNK in response to vincristine was also particularly impaired (Figure 4a, top two panels), when intracellular O-GlcNAc levels were increased by pre-culture with GlcNAc and uridine (Figure 4a, bottom panel).…”

Section: Resultsmentioning

confidence: 99%

Aberrant O-GlcNAcylation characterizes chronic lymphocytic leukemia

et al. 2010

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“…[75] It either has been or is currently being evaluated in 37 clinical trials for various types of cancer. [76] It has also been shown to enhance memory and learning in animals, reduce Ab peptide build-up in mice,i nduce synaptic contact formation, and reduce postischemic/hypoxic damage resulting from stroke. [77] As such, it has been evaluated in two clinical trials for Alzheimers disease,w ith another trial currently ongoing.I na ddition, bryostatin 1i s also currently being evaluated for HIV/AIDS treatment in yet another clinical trial.…”

Section: Angewandte Chemiementioning

confidence: 99%

Capturing Biological Activity in Natural Product Fragments by Chemical Synthesis

2016

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Natural products have had an immense influence on science and have directly led to the introduction of many drugs. Organic chemistry, and its unique ability to tailor natural products through synthesis, provides an extraordinary approach to unlock the full potential of natural products. In this Review, an approach based on natural product derived fragments is presented that can successfully address some of the current challenges in drug discovery. These fragments often display significantly reduced molecular weights, reduced structural complexity, a reduced number of synthetic steps, while retaining or even improving key biological parameters such as potency or selectivity. Examples from various stages of the drug development process up to the clinic are presented. In addition, this process can be leveraged by recent developments such as genome mining, antibody–drug conjugates, and computational approaches. All these concepts have the potential to identify the next generation of drug candidates inspired by natural products.

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“…18 A C-series custom antibody array for 21 STAT3-activating cytokines and growth factors was purchased from Ray Biotech (Norcross, GA).…”

Section: Immunophenotyping and Membrane Tnf (Mtnf)-a Detectionmentioning

confidence: 99%

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

Shi

McCaw

et al. 2015

Blood

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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)

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Prolonging microtubule dysruption enhances the immunogenicity of chronic lymphocytic leukaemia cells

Cited by 25 publications

References 33 publications

Aberrant O-GlcNAcylation characterizes chronic lymphocytic leukemia

Aberrant O-GlcNAcylation characterizes chronic lymphocytic leukemia

Capturing Biological Activity in Natural Product Fragments by Chemical Synthesis

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

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