Toll-like receptor 4 signaling pathway is correlated with pathophysiological characteristics of AML patients and its inhibition using TAK-242 suppresses AML cell proliferation

Baakhlagh, Sedigheh; Kashani, Bahareh; Zandi, Zahra; Bashash, Davood; Moradkhani, Malihe; Nasrollahzadeh, Ali; Marjan, Yaghmaei; Mousavi, Seyed Asadollah; Ghaffari, Seyed H.

doi:10.1016/j.intimp.2020.107202

Cited by 9 publications

(13 citation statements)

References 49 publications

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“…This is similar to the previous functional study [ 23 ] that also described a relatively stronger prognostic impact of TLR1/2 responses. The prognostic impact of the TLR-associated cytokine response was also supported by a smaller study only investigating interleukin 6 (IL6) expression [ 14 ], and additional experimental studies in AML cell lines suggested that TLR4 inhibition had antiproliferative and proapoptotic effects mediated through upregulation of p21, TP53 (tumor protein p53, and BAD (BCL2 associated agonist of cell death). TLR4 expression is regulated at the transcriptional level by a suppressive effect of the Interferon regulatory factor 1 (IRF1), and studies in AML cell lines suggest that this factor also suppresses expression of the adhesion molecule ICAM1 (intercellular adhesion molecule 1)and in addition has an antiapoptotic effect [ 28 ].…”

Section: Tlr4 In Acute Myeloid Leukemiamentioning

confidence: 98%

“…It is involved in the development of lymphoid cells [ 12 ], and it is expressed by various stromal cells [ 8 ]. It is also expressed by AML [ 13 , 14 ] and preleukemic myelodysplastic syndrome (MDS) cells [ 15 ]. Thus, TLR4 targeting will probably have both direct and indirect effects on leukemic hematopoiesis [ 8 , 14 , 16 ].…”

Section: The Structure Ligand Binding and Downstream Signaling Of Tlr4mentioning

confidence: 99%

“…It is also expressed by AML [ 13 , 14 ] and preleukemic myelodysplastic syndrome (MDS) cells [ 15 ]. Thus, TLR4 targeting will probably have both direct and indirect effects on leukemic hematopoiesis [ 8 , 14 , 16 ].…”

Section: The Structure Ligand Binding and Downstream Signaling Of Tlr4mentioning

confidence: 99%

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Toll-like Receptor 4, Osteoblasts and Leukemogenesis; the Lesson from Acute Myeloid Leukemia

2022

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Toll-like receptor 4 (TLR4) is a pattern-recognizing receptor that can bind exogenous and endogenous ligands. It is expressed by acute myeloid leukemia (AML) cells, several bone marrow stromal cells, and nonleukemic cells involved in inflammation. TLR4 can bind a wide range of endogenous ligands that are present in the bone marrow microenvironment. Furthermore, the TLR4-expressing nonleukemic bone marrow cells include various mesenchymal cells, endothelial cells, differentiated myeloid cells, and inflammatory/immunocompetent cells. Osteoblasts are important stem cell supporting cells localized to the stem cell niches, and they support the proliferation and survival of primary AML cells. These supporting effects are mediated by the bidirectional crosstalk between AML cells and supportive osteoblasts through the local cytokine network. Finally, TLR4 is also important for the defense against complicating infections in neutropenic patients, and it seems to be involved in the regulation of inflammatory and immunological reactions in patients treated with allogeneic stem cell transplantation. Thus, TLR4 has direct effects on primary AML cells, and it has indirect effects on the leukemic cells through modulation of their supporting neighboring bone marrow stromal cells (i.e., modulation of stem cell niches, regulation of angiogenesis). Furthermore, in allotransplant recipients TLR4 can modulate inflammatory and potentially antileukemic immune reactivity. The use of TLR4 targeting as an antileukemic treatment will therefore depend both on the biology of the AML cells, the biological context of the AML cells, aging effects reflected both in the AML and the stromal cells and the additional antileukemic treatment combined with HSP90 inhibition.

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Section: Tlr4 In Acute Myeloid Leukemiamentioning

confidence: 98%

Section: The Structure Ligand Binding and Downstream Signaling Of Tlr4mentioning

confidence: 99%

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Toll-like Receptor 4, Osteoblasts and Leukemogenesis; the Lesson from Acute Myeloid Leukemia

2022

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“…The obtained results showed that the applied inhibitor not only stopped the proliferation of all cell lines of leukemia, but also changed the distribution of their cell cycle. Additionally, it was noticed that, in AML patients with poor prognosis, there is a much higher expression of TLR4, MyD88, and NF-кB mRNA [ 292 ]. In light of this evidence, it seems advantageous to continue research on TLR4 and its inhibitor, as it may be a good strategy for the treatment of TLR4-expressing AML in the future.…”

Section: Future Perspectives In the Treatment Of All Or Amlmentioning

confidence: 99%

Insights into Modern Therapeutic Approaches in Pediatric Acute Leukemias

Panuciak

Margas

MAKOWSKA

et al. 2022

Cells

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Pediatric cancers predominantly constitute lymphomas and leukemias. Recently, our knowledge and awareness about genetic diversities, and their consequences in these diseases, have greatly expanded. Modern solutions are focused on mobilizing and impacting a patient’s immune system. Strategies to stimulate the immune system, to prime an antitumor response, are of intense interest. Amid those types of therapies are chimeric antigen receptor T (CAR-T) cells, bispecific antibodies, and antibody–drug conjugates (ADC), which have already been approved in the treatment of acute lymphoblastic leukemia (ALL)/acute myeloid leukemia (AML). In addition, immune checkpoint inhibitors (ICIs), the pattern recognition receptors (PRRs), i.e., NOD-like receptors (NLRs), Toll-like receptors (TLRs), and several kinds of therapy antibodies are well on their way to showing significant benefits for patients with these diseases. This review summarizes the current knowledge of modern methods used in selected pediatric malignancies and presents therapies that may hold promise for the future.

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“…Interestingly, we realized that the inhibition of TLR4 boosted the cell cytotoxicity of all drugs, which indicates the fact TLR4 would confer chemo-resistance to a broad range of anti-cancer agents. 51,52 F…”

Section: Tlr-mediated Anti-apoptotic Effectsmentioning

confidence: 99%

Toll‐like receptors (TLRs): An old family of immune receptors with a new face in cancer pathogenesis

Mokhtari

Pourbagheri‐Sigaroodi

Zafari

et al. 2020

J Cellular Molecular Medi

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Innate immunity not only represents the first line of defence against invading microbial pathogens but also is the first step towards the activation and stimulation of adaptive immunity. Upon exposure to bacteria, viruses, protozoa and fungi, innate immune cells including neutrophils, monocytes, macrophages, dendritic cells (DCs), natural killer (NK) cells and the complement system are activated. The response of the innate immunity to microbial pathogens relies on the specific host-receptor detection of pathogen-and danger-derived molecular signatures, known as PAMPs and DAMPs, respectively. When PAMPs and DAMPs are recognized by germline-encoded pattern-recognition receptors (PRRs), different types of cytokines would be released, which in turn attract secondary defensive immune cells. In the long list of PRRs, Tolllike receptors (TLRs) are the most important ones. TLRs are one of the largest and most well-studied families of PRRs, which were first recognized in the fruit fly, Drosophila melanogaster. 1 Not only these receptors are one of the main components of innate immunity, infection diseases, and inflammatory conditions, but also they act as a bridge between innate and adaptive immunity. Apart from regulatory role in immune responses, TLRs have a hand in tissue homeostasis maintenance by regulating tissue repair and regeneration. But the mystery behind TLR functions in the cells was not limited only to these findings, and there was some evidence supporting the fact that they might have

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Toll-like receptor 4 signaling pathway is correlated with pathophysiological characteristics of AML patients and its inhibition using TAK-242 suppresses AML cell proliferation

Cited by 9 publications

References 49 publications

Toll-like Receptor 4, Osteoblasts and Leukemogenesis; the Lesson from Acute Myeloid Leukemia

Toll-like Receptor 4, Osteoblasts and Leukemogenesis; the Lesson from Acute Myeloid Leukemia

Insights into Modern Therapeutic Approaches in Pediatric Acute Leukemias

Toll‐like receptors (TLRs): An old family of immune receptors with a new face in cancer pathogenesis

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