Toll‐like Receptors (TLRs) are expressed by myeloid leukaemia cell lines, but fail to trigger differentiation in response to the respective TLR ligands

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

“…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.…”

“…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.…”

“…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.…”

“…29,30 They were proven to be safe and well-tolerated by patients and did not seem to induce adverse effects such as tumor cell proliferation and survival, which have been reported in some in vitro studies. 25,27,29,31 However, the TLR9 agonists used as single agents or even combined with vaccinations failed to overcome strongly immunosuppressive tumor environment in cancer patients. 29,32 We have shown previously that STAT3 is an important negative feedback regulator that restricts the immunostimulatory effects of several TLRs, including TLR9.…”

siRNAs encapsulated in recombinant capsid protein derived from Dengue serotype 2 virus inhibits the four serotypes of the virus and proliferation of cancer cells

“…3B and C). Since K-562 is a myeloid cell line that expresses Toll Like Receptors (TLRs) that are known to bind double stranded RNA molecules (Okamoto et al, 2009;Kariko et al, 2004), it is possible that the modest increase in Mean Fluorescence Intensity (over untreated control) observed in these cells treated with Cy3 labelled siRNA alone, is due to binding of the siRNA to the cell surface. In addition, fluorescence microscopy studies showed intracellular distribution of siRNA in cells treated with D2C encapsulated, Cy3 labelled siRNA, but not in those treated with naked Cy3 labelled siRNA.…”