A threshold level of TLR9 mRNA predicts cellular responsiveness to CpG-ODN in haematological and non-haematological tumour cell lines

Assaf, Areej M.; Esteves, Helia; Curnow, S. John; Browning, Michael

doi:10.1016/j.cellimm.2009.06.003

Cited by 17 publications

(15 citation statements)

References 34 publications

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“…Our studies confirmed the feasibility of using CpG(A)-siRNAs for targeting human TLR9-expressing cells such as pDCs, mDCs, B cells, and several myeloid and B-cell malignancies. [25][26][27][37][38][39] We have demonstrated that although TLR9 Ϫ cells such as monocytes are still able to quickly internalize CpG(A)-siRNA, in the absence of TLR9 expression, conjugates do not induce RNAi. Our independent studies delineating the molecular mechanism of intracellular CpG-siRNA processing suggest that TLR9 may in fact participate For personal use only.…”

Section: Discussionmentioning

confidence: 99%

“…33 The mechanism of STAT3 activation by class-B CpGODNs in human hematopoietic cells is likely to depend on up-regulation of cytokines such as IL-6 and IL-10, as shown in this and other studies. 23,26,32 The signaling cross-talk within the tumor microenvironment further enhances STAT3 signaling, dampening the immunostimulatory activity of TLR agonists. 33 In contrast, in the present study, we did not detect increased levels of STAT3-inducing cytokines in human PBMCs cultured with unconjugated CpG(A) ODNs or CpG(A)-siRNAs.…”

Section: Discussionmentioning

confidence: 99%

“…16,36,42 In contrast, our approach used a ligand to intracellular TLR9 receptor that is ubiquitously expressed in B-cell malignancies and AML. [25][26][27] Dicer RNase, which is critical for uncoupling of CpG-siRNA conjugates, is also commonly expressed in normal and transformed B cells and in the majority of clinical AML samples. 43,44 Our results demonstrate that repeated administration of CpG(A)-siRNAs specific for oncogenic and/or prosurvival genes such as STAT3 or BCL-X L can induce tumor cell apoptosis and inhibit the growth of several xenotransplanted human MM and AML tumors.…”

Section: Discussionmentioning

confidence: 99%

“…23,24 TLR9 is commonly expressed in many hematologic malignancies, including AML, MM, and BCL. [25][26][27][28] Activation of TLR9 was shown either to enhance antigen-presenting functions or to induce apoptosis of primary malignant B cells. 27,29 TLR9 agonists have been tested in numerous clinical trials as anticancer reagents for the treatment of hematologic malignancies including AML, MM, and BCL.…”

Section: Introductionmentioning

confidence: 99%

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TLR9-mediated siRNA delivery for targeting of normal and malignant human hematopoietic cells in vivo

Zhang¹,

Hossain²,

Nechaev

et al. 2013

Blood

119

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• CpG(A)-siRNA oligonucleotides allow for targeting genes specifically in human TLR9 ϩ immune cells and blood cancer cells.• Tumoricidal and immunostimulatory properties of CpG(A)-STAT3 siRNA provide a novel therapeutic opportunity for hematologic malignancies.STAT3 operates in both cancer cells and tumor-associated immune cells to promote cancer progression. As a transcription factor, it is a highly desirable but difficult target for pharmacologic inhibition. We have recently shown that the TLR9 agonists CpG oligonucleotides can be used for targeted siRNA delivery to mouse immune cells. In the present study, we demonstrate that a similar strategy allows for targeted gene silencing in both normal and malignant human TLR9 ؉ hematopoietic cells in vivo. We have developed new human cell-specific CpG(A) - IntroductionThe proliferation and survival of the majority of hematologic cancers depends on constitutive activity of STAT transcription factors. 1,2 The first evidence linking STAT activity with human blood cancer was derived from studies on multiple myeloma (MM). Permanent activity of STAT3 observed in myeloma cells was critical for their survival because of up-regulation of antiapoptotic BCL-X L protein. 3 Later reports identified constitutive activation of STAT3 not only in myeloma but also in other hematologic malignancies, with the highest frequency in B-cell lymphoma (BCL) and acute myeloid leukemia (AML) patient blasts. 1,4,5 The presence of activated STAT3 in leukemic blasts was associated with decreased disease-free survival of AML patients. 4 As a point of convergence for downstream signaling from cytokine and growth factor receptors, STAT3 plays a critical role in mediating cross-talk within the tumor microenvironment, which promotes tumor immune tolerance, vascularization, and metastasis. 6 Because STAT3 operates in both cancer cells and nonmalignant tumorassociated cells, it represents a highly desirable target for cancer therapy. 6 These important findings instigated numerous attempts to develop STAT3 inhibitors; however, pharmacologic inhibition of a protein lacking enzymatic activity is challenging. 4,7 An additional complication is the close structural similarity between oncogenic STAT3 and functionally distinct STAT1, a transcriptional factor critical for generation of antitumor immunity by IFNs. 8,9 The tyrosine kinase inhibitors upstream from STAT3, such as JAK, SRC, c-KIT, and FLT3 in leukemia, gained attention as promising blood cancer therapeutics. 4 However, the effect of small-molecule drugs, including FLT3 inhibitors, in most clinical trials was short-lived. 10,11 Other conventional treatment regimens for hematologic malignancies are limited by the high toxicity to normal tissues, development of drug resistance, and low disease-free survival rates. For personal use only. on May 11, 2018. by guest www.bloodjournal.org FromThe emergence of therapeutic strategies based on RNA interference (RNAi) created a unique opportunity to silence any diseaserelated target gene. 13,14 The major obstacle ...

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Section: Discussionmentioning

confidence: 99%

Section: Discussionmentioning

confidence: 99%

Section: Discussionmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

See 2 more Smart Citations

TLR9-mediated siRNA delivery for targeting of normal and malignant human hematopoietic cells in vivo

Zhang¹,

Hossain²,

Nechaev

et al. 2013

Blood

119

View full text Add to dashboard Cite

show abstract

“…Taken together, these data point to a specific mechanism, in which the threshold RLT2 level in 4MS condition is not sufficient to activate phas-GUS expression in leaves, and suggest that Pv-ALF-dependent induction of RLT2 is necessary to trigger phas-GUS expression. A similar threshold mechanism for the basal level of p53 and toll like receptor 9 expression has recently been described for the activation of apoptosis and immune responses in human cells (Assaf et al, 2009;Kracikova et al, 2013).…”

Section: Rlt2 and Ail5 Are Required For Efficient Activation Of Phas-mentioning

confidence: 99%

Gene Networks and Chromatin and Transcriptional Regulation of the Phaseolin Promoter in Arabidopsis

et al. 2013

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The complete lack of seed storage protein expression in vegetative tissues and robust expression during embryogenesis makes seed development an ideal system to study tissue-specific expression of genes. The promoter for the Phaseolin (phas) gene, which encodes the major seed storage protein in bean (Phaseolus vulgaris), is activated in two sequential steps: Phaseolus vulgaris ABI3-like factor (Pv-ALF)-dependent potentiation and abscisic acid-mediated activation. In this study, a heterologous in vivo Pv-ALF/phas-GUS (for b-glucuronidase) expression system in transgenic Arabidopsis thaliana leaves was used in conjunction with the powerful RNA-Seq approach to capture transcriptional landscapes of phas promoter expression. Remarkably, expression of over 1300 genes from 11 functional categories coincided with changes in the transcriptional status of the phas promoter. Gene network analysis of induced genes and artificial microRNA-mediated loss-of-function genetic assays identified transcriptional regulators RINGLET 2 (RLT2) and AINTEGUMENTA-LIKE 5 (AIL5) as being essential for phas transcription. Pv-ALF binding to the RLT2 and AIL5 promoter regions was confirmed by electrophoretic mobility shift assay. RLT2 and AIL5 knockdown lines displayed reduced expression of several endogenous seed genes, suggesting that these factors are involved in activation of endogenous Arabidopsis seed storage gene expression. Overall, the identification of these key factors involved in phas activation provides important insight into the two-step transcriptional regulation of seed-specific gene expression.

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Therapeutic applications of toll-like receptors (TLRs) agonists in AML

Wang

Lan

et al. 2022

Clin Transl Oncol

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A threshold level of TLR9 mRNA predicts cellular responsiveness to CpG-ODN in haematological and non-haematological tumour cell lines

Cited by 17 publications

References 34 publications

TLR9-mediated siRNA delivery for targeting of normal and malignant human hematopoietic cells in vivo

TLR9-mediated siRNA delivery for targeting of normal and malignant human hematopoietic cells in vivo

Gene Networks and Chromatin and Transcriptional Regulation of the Phaseolin Promoter in Arabidopsis

Therapeutic applications of toll-like receptors (TLRs) agonists in AML

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