Interferon γ is a STAT1-dependent direct inducer of BCL6 expression in imatinib-treated chronic myeloid leukemia cells

Madapura, Harsha S; Nagy, Noémi; Ujvári, Dorina; Kallas, Tomasz; Kröhnke, Marijke C L; Amu, Sylvie; Björkholm, Magnus; Stenke, Leif; Mandal, Pijus K.; McMurray, John S.; Keszei, Márton; Westerberg, Lisa S.; Cheng, Huimin; Xue, Fengtian; Klein, George; Klein, Eva; Salamon, Dániel

doi:10.1038/onc.2017.85

Cited by 40 publications

(38 citation statements)

References 50 publications

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“…These data support a protumorigenic effect of IFN-γ in CML and suggest that IFN-γ may contribute to TKI resistance. Their data suggest that combining TKIs with inhibitors of BCL6 or MCL1 is a potential approach to eradicate CML stem cells ( 45 ).…”

Section: Type II Ifn (Ifn-γ)mentioning

confidence: 99%

Inflammatory Signaling Pathways in Preleukemic and Leukemic Stem Cells

2017

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Hematopoietic stem cells (HSCs) are a rare subset of bone marrow cells that usually exist in a quiescent state, only entering the cell cycle to replenish the blood compartment, thereby limiting the potential for errors in replication. Inflammatory signals that are released in response to environmental stressors, such as infection, trigger active cycling of HSCs. These inflammatory signals can also directly induce HSCs to release cytokines into the bone marrow environment, promoting myeloid differentiation. After stress myelopoiesis is triggered, HSCs require intracellular signaling programs to deactivate this response and return to steady state. Prolonged or excessive exposure to inflammatory cytokines, such as in prolonged infection or in chronic rheumatologic conditions, can lead to continued HSC cycling and eventual HSC loss. This promotes bone marrow failure, and can precipitate preleukemic states or leukemia through the acquisition of genetic and epigenetic changes in HSCs. This can occur through the initiation of clonal hematopoiesis, followed by the emergence preleukemic stem cells (pre-LSCs). In this review, we describe the roles of multiple inflammatory signaling pathways in the generation of pre-LSCs and in progression to myelodysplastic syndrome (MDS), myeloproliferative neoplasms, and acute myeloid leukemia (AML). In AML, activation of some inflammatory signaling pathways can promote the cycling and differentiation of LSCs, and this can be exploited therapeutically. We also discuss the therapeutic potential of modulating inflammatory signaling for the treatment of myeloid malignancies.

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Section: Type II Ifn (Ifn-γ)mentioning

confidence: 99%

Inflammatory Signaling Pathways in Preleukemic and Leukemic Stem Cells

2017

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“…Signal transduction and transcriptional activator 1 (STAT1) is encoded by STAT1 gene in human being. Specific expression of STAT1 can be mediated by some cytokines, such as IFN-α ( 69 , 70 ), IFN-γ ( 71 , 72 ), or IL-6 ( 73 , 74 ). IFN-α binds receptor and triggers STAT signal via its phosphorylation and activation of STAT1 and STAT2.…”

Section: Pos Affect Mitogen-activated Protein Kinases (Mapk) Signalinmentioning

confidence: 99%

Pectin Oligosaccharides Ameliorate Colon Cancer by Regulating Oxidative Stress- and Inflammation-Activated Signaling Pathways

et al. 2018

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Colon cancer (CC) is the third common neoplasm worldwide, and it is still a big challenge for exploring new effective medicine for treating CC. Natural product promoting human health has become a hot topic and attracted many researchers recently. Pectin, a complex polysaccharide in plant cell wall, mainly consists of four major types of polysaccharides: homogalacturonan, xylogalacturonan, rhamnogalacturonan I and II, all of which can be degraded into various pectin oligosaccharides (POS) and may provide abundant resource for exploring potential anticancer drugs. POS have been regarded as a novel class of potential functional food with multiple health-promoting properties. POS have antibacterial activities against some aggressive and recurrent bacterial infection and exert beneficial immunomodulation for controlling CC risk. However, the molecular functional role of POS in the prevention of CC risk and progression remains doubtful. The review focuses on antioxidant and anti-inflammatory roles of POS for promoting human health by regulating some potential oxidative and inflammation-activated pathways, such as ATP-activated protein kinase (AMPK), nuclear factor erythroid-2-related factor-2 (Nrf2), and nuclear factor-κB (NF-κB) pathways. The activation of these signaling pathways increases the antioxidant and antiinflammatory activities, which will result in the apoptosis of CC cells or in the prevention of CC risk and progression. Thus, POS may inhibit CC development by affecting antioxidant and antiinflammatory signaling pathways AMPK, Nrf2, and NF-κB. However, POS also can activate signal transduction and transcriptional activator 1 and 3 signaling pathway, which will reduce antioxidant and anti-inflammatory properties and promote CC progression. Specific structural and structurally modified POS may be associated with their functions and should be deeply explored in the future. The present review paper lacks the important information for the linkage between the specific structure of POS and its function. To further explore the effects of prebiotic potential of POS and their derivatives on human immunomodulation in the prevention of CC, the specific POS with a certain degree of polymerization or purified polymers are highly demanded to be performed in clinical practice.

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“…CML can be treated using a combination of these 11 genes. For example, studies have shown that the combination of TKIs with BCL6 and MCL1 inhibitors may lead to the complete eradication of CML stem cells (Madapura et al, ).…”

Section: Discussionmentioning

confidence: 99%

Identification of key candidate targets and pathways for the targeted treatment of leukemia stem cells of chronic myelogenous leukemia using bioinformatics analysis

Liu

Zhuang

et al. 2019

Molec Gen & Gen Med

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Background Chronic myelogenous leukemia (CML) is a myeloproliferative neoplasm that arises from the acquisition of constitutively active BCR‐ABL tyrosine kinase in hematopoietic stem cells. The persistence of bone marrow leukemia stem cells (LSCs) is the main cause of TKI resistance and CML relapse. Therefore, finding a key target or pathway to selectively target LSCs is of great significance for the thorough treatment of CML. Methods In this study, we aimed to identify key microRNAs, microRNA targets and pathways for the treatment of CML LSCs by integrating analyses of three microarray data profiles. We identified 51 differentially expressed microRNAs through integrated analysis of GSE90773 and performed functional gene predictions for microRNAs. Then, GSE11889 and GSE11675 were integrated to obtain differentially expressed genes (DEGs), and the overlapping DEGs were used as models to identify predictive functional genes. Finally, we identified 116 predictive functional genes. Clustering and significant enrichment analysis of 116 genes was based on function and signaling pathways. Subsequently, a protein interaction network was constructed, and module analysis and topology analysis were performed on the network. Results A total of 11 key candidate targets and 33 corresponding microRNAs were identified. The key pathways were mainly concentrated on the PI3K/AKT, Ras, JAK/STAT, FoxO and Notch signaling pathways. We also found that LSCs negatively regulated endogenous and exogenous apoptotic pathways to escape from apoptosis. Conclusion We identified key candidate targets and pathways for CML LSCs through bioinformatics methods, which improves our understanding of the molecular mechanisms of CML LSCs. These candidate genes and pathways may be therapeutic targets for CML LSCs.

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Interferon γ is a STAT1-dependent direct inducer of BCL6 expression in imatinib-treated chronic myeloid leukemia cells

Cited by 40 publications

References 50 publications

Inflammatory Signaling Pathways in Preleukemic and Leukemic Stem Cells

Inflammatory Signaling Pathways in Preleukemic and Leukemic Stem Cells

Pectin Oligosaccharides Ameliorate Colon Cancer by Regulating Oxidative Stress- and Inflammation-Activated Signaling Pathways

Identification of key candidate targets and pathways for the targeted treatment of leukemia stem cells of chronic myelogenous leukemia using bioinformatics analysis

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