Inhibition of Type 4 Cyclic Nucleotide Phosphodiesterase Blocks Intracellular TLR Signaling in Chronic Lymphocytic Leukemia and Normal Hematopoietic Cells

Tan, Ying; Watkins, Amanda A.; Freeman, Benjamin; Meyers, John A.; Rifkin, Ian R.; Lerner, Adam

doi:10.4049/jimmunol.1401854

Cited by 13 publications

(11 citation statements)

References 74 publications

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“…This raises the interesting possibility that levels of circulating DNA could affect drug sensitivity in these B-cell malignancies. Although CpG-ODN is often thought of as a surrogate for bacterial/viral DNA, TLR9 can be activated by cellular DNA, especially mitochondrial DNA, generated during cytolysis 28 . Large amounts of DNA have been detected in the plasma/serum of patients of various B-cell malignancies, including CLL 61,62 , with highest levels found in relapsed patient samples 61 .…”

Section: 0 Discussionmentioning

confidence: 99%

Microenvironmental agonists generate de novo phenotypic resistance to combined ibrutinib plus venetoclax in CLL and MCL

Jayappa

Portell²,

Gordon

et al. 2017

Blood Advances

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De novo resistance and rapid recurrence often characterize responses of B-cell malignancies to ibrutinib (IBR), indicating a need to develop drug combinations that block compensatory survival signaling and give deeper, more durable responses. To identify such combinations, we previously performed a combinatorial drug screen and identified the Bcl-2 inhibitor venetoclax (VEN) as a promising partner for combination with IBR in Mantle Cell Lymphoma (MCL). We have opened a multi-institutional clinical trial to test this combination. However, analysis of primary samples from patients with MCL as well as chronic lymphocytic leukemia (CLL) revealed unexpected heterogeneous de novo resistance even to the IBR+VEN combination. In the current study, we demonstrate that resistance to the combination can be generated by microenvironmental agonists: IL-10, CD40L and, most potently, CpG-oligodeoxynucleotides (CpG-ODN), which is a surrogate for unmethylated DNA and a specific agonist for TLR9 signaling. Incubation with these agonists caused robust activation of NF-κB signaling, especially alternative NF-κB, which led to enhanced expression of the anti-apoptotic proteins Mcl-1, Bcl-xL, and survivin, thus decreasing dependence on Bcl-2. Inhibitors of NF-κB signaling blocked overexpression of these anti-apoptotic proteins and overcame resistance. Inhibitors of Mcl-1, Bcl-xL, or survivin also overcame this resistance, and showed synergistic benefit with the IBR+VEN combination. We conclude that microenvironmental factors, particularly the TLR9 agonist, can generate de novo resistance to the IBR+VEN combination in CLL and MCL cells. This signaling pathway presents targets for overcoming drug resistance induced by extrinsic microenvironmental factors in diverse B-cell malignancies.

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Section: 0 Discussionmentioning

confidence: 99%

Microenvironmental agonists generate de novo phenotypic resistance to combined ibrutinib plus venetoclax in CLL and MCL

Jayappa

Portell²,

Gordon

et al. 2017

Blood Advances

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“…The role of cAMP is quite different in diverse types of lymphoma. PDE4 inhibitors block intracellular TLR signaling and promote apoptosis of chronic lymphocytic leukemia (CLL) cells through increasing cAMP concentration [ 112 , 113 ]. Interestingly, PDE4 inhibitors induce apoptosis in B cell CLL but not in T cell CLL or normal circulating hematopoietic cells, probably due to that PDE4 inhibitors only augment glucocorticoid receptor and cAMP levels in B cell CLL [ 114 , 115 ].…”

Section: The Roles Of Camp–pka–creb Signaling Pathway In Tumorsmentioning

confidence: 99%

Complex roles of cAMP–PKA–CREB signaling in cancer

et al. 2020

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Cyclic adenosine monophosphate (cAMP) is the first discovered second messenger, which plays pivotal roles in cell signaling, and regulates many physiological and pathological processes. cAMP can regulate the transcription of various target genes, mainly through protein kinase A (PKA) and its downstream effectors such as cAMP-responsive element binding protein (CREB). In addition, PKA can phosphorylate many kinases such as Raf, GSK3 and FAK. Aberrant cAMP–PKA signaling is involved in various types of human tumors. Especially, cAMP signaling may have both tumor-suppressive and tumor-promoting roles depending on the tumor types and context. cAMP–PKA signaling can regulate cancer cell growth, migration, invasion and metabolism. This review highlights the important roles of cAMP–PKA–CREB signaling in tumorigenesis. The potential strategies to target this pathway for cancer therapy are also discussed.

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“…Previously, we have shown that an SLE patient's serum (SLE1), which contains anti-Sm Ab and anti-RNP Ab (Table I), activates mouse plasmacytoid dendritic cells to induce type I IFN through FcgR and TLR7 signaling (11). RNA-containing ICs made by Sm/ RNP Ag and SLE1 serum activated PBMC to induce type I IFN (29). We used a similar approach to stimulate neutrophils from lupus patients with Sm/RNP-containing ICs ( Fig.…”

Section: Ics Activate Neutrophils From Lupus Patientsmentioning

confidence: 99%

Lupus-Associated Immune Complexes Activate Human Neutrophils in an FcγRIIA-Dependent but TLR-Independent Response

Bonegio

Beaudette-Zlatanova

York

et al. 2019

The Journal of Immunology

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Systemic lupus erythematosus (SLE) is an autoimmune disease characterized by the presence of autoantibodies against nucleic acids and nucleoproteins. Anti-dsDNA Abs are considered a hallmark of SLE, and previous studies have indicated that nucleic acid–containing immune complexes (ICs) induce B cell and dendritic cell activation in a TLR-dependent process. How ICs containing nucleic acids affect neutrophil function has not been well investigated. In this study, we report that nucleic acid–containing ICs derived from the sera of SLE patients induce human and mouse neutrophil activation through TLR-independent mechanisms. Soluble ICs containing Sm/RNP, an RNA Ag, activate human neutrophils to produce reactive oxygen species (ROS) and IL-8. In contrast, ICs containing DNA have to be immobilized to efficiently activate neutrophils. We found that deleting TLR7 or TLR9, the receptors for RNA and DNA, had no effect on mouse neutrophil activation induced by RNA-containing and immobilized DNA–containing ICs. Binding of ICs are mediated through FcγRIIA and FcγRIIIB. However, neutrophil activation induced by RNA- and DNA-containing ICs requires FcγRIIA, as blocking FcγRIIA inhibited ROS release from neutrophils. RNA-containing ICs induce calcium flux, whereas TLR7/8 ligand R848 do not. Surprisingly, chloroquine inhibits calcium flux induced by RNA-containing ICs, suggesting that this lesser known function of chloroquine is involved in the neutrophil activation induced by ICs. These data indicate the SLE-derived ICs activate neutrophils to release ROS and chemokines in an FcγRIIA-dependent and TLR7- and TLR9-independent manner that likely contributes to local tissue inflammation and damage.

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Inhibition of Type 4 Cyclic Nucleotide Phosphodiesterase Blocks Intracellular TLR Signaling in Chronic Lymphocytic Leukemia and Normal Hematopoietic Cells

Cited by 13 publications

References 74 publications

Microenvironmental agonists generate de novo phenotypic resistance to combined ibrutinib plus venetoclax in CLL and MCL

Microenvironmental agonists generate de novo phenotypic resistance to combined ibrutinib plus venetoclax in CLL and MCL

Complex roles of cAMP–PKA–CREB signaling in cancer

Lupus-Associated Immune Complexes Activate Human Neutrophils in an FcγRIIA-Dependent but TLR-Independent Response

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