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The editorial in Frontiers in Oncology discusses the molecular characterization of acute leukemias, focusing on leukemia-initiating cells and the influence of the tissue microenvironment. Various studies highlighted in the editorial explore different aspects of acute leukemias, such as identifying biomarkers, treatment approaches, and prognostic factors. The research aims to enhance the understanding of the molecular mechanisms underlying acute leukemias to develop more effective treatment strategies and improve patient outcomes. The authors express gratitude to all contributors and emphasize the importance of continued research in this field. [Extracted from the article]

Inflammation is activated by diverse triggers that induce the expression of cytokines and adhesion molecules, which permit a succession of molecules and cells to deliver stimuli and functions that help the immune system clear the primary cause of tissue damage, whether this is an infection, a tumor, or a trauma. During inflammation, short-term changes in the expression and secretion of strong mediators of inflammation occur, while long-term changes occur to specific groups of cells. Long-term changes include cellular transdifferentiation for some types of cells that need to regenerate damaged tissue, as well as death for specific immune cells that can be detrimental to tissue integrity if they remain active beyond the boundaries of essential function. The transcriptional regulator NFκB enables some of the fundamental gene expression changes during inflammation, as well as during tissue development. During recurrence of malignant disease, cell stress-induced alterations enable the growth of cancer cell clones that are substantially resistant to therapeutic intervention and to the immune system. A number of those alterations occur due to significant defects in feedback signal cascades that control the activity of NFκB. Specifically, cell stress contributes to feedback defects as it overrides modules that otherwise control inflammation to protect host tissue. NFκB is involved in both the suppression and promotion of cancer, and the key distinctive feature that determines its net effect remains unclear. This paper aims to provide a clear answer to at least one aspect of this question, namely the mechanism that enables a divergent response of cancer cells to critical inflammatory stimuli and to cell stress in general. [ABSTRACT FROM AUTHOR]

Epithelial–mesenchymal transition (EMT) is a metabolic process that confers phenotypic flexibility to cells and the ability to adapt to new functions. This transition is critical during embryogenesis and is required for the differentiation of many tissues and organs. EMT can also be induced in advanced-stage cancers, leading to further malignant behavior and chemotherapy resistance, resulting in an unfavorable prognosis for patients. Although EMT was long considered and studied only in solid tumors, it has been shown to be involved in the pathogenesis of hematological malignancies, including acute leukemias. Indeed, there is increasing evidence that EMT promotes the progression of acute leukemias, leading to the emergence of a more aggressive phenotype of the disease, and also causes chemotherapy resistance. The current literature suggests that the levels and activities of EMT inducers and markers can be used to predict prognosis, and that targeting EMT in addition to conventional therapies may increase treatment success in acute leukemias. [ABSTRACT FROM AUTHOR]

Simple Summary: OGG1-enabled NFκB activity can promote cancer progression via a number of key mechanisms that include phenotypic transitions of cancer and stromal cells, expression and secretion of molecules that modulate innate immunity, and alteration of the vascular network. Under oxidative stress, the supraphysiological levels of nongenotoxic 8-oxoGua, along with redox inactivation of OGG1 via cysteine oxidation and potential dimerization, provide multiple interfaces with redox-activated/modulated NFκB and other transacting factors, including Myc. This promotes not only cell proliferation, the expression of innate immune genes, and angiogenesis but also the metastatic capability of cells involving the expression of epithelial–mesenchymal transition genes. Mounting evidence supports the idea that increased levels of oxidative stress play a crucial role in the onset and progression of solid and lymphoid malignancies. This is achieved by gaining mutations and by activating signaling pathways that promote cell survival, cell proliferation, and resistance to treatment modalities. 8-oxoguanine glycosylase 1 (OGG1), which was initially identified as the enzyme that catalyzes the first step in the DNA base excision repair pathway, is now also recognized as a modulator of gene expression. What is important for cancer is that OGG1 acts as a modulator of NFκB-driven gene expression. Specifically, oxidant stress in the cell transiently halts enzymatic activity of substrate-bound OGG1. The stalled OGG1 facilitates DNA binding of transactivators, such as NFκB to their cognate sites, enabling the expression of cytokines and chemokines, with ensuing recruitment of inflammatory cells. Recently, we highlighted chief aspects of OGG1 involvement in regulation of gene expression, which hold significance in lung cancer development. However, OGG1 has also been implicated in the molecular underpinning of acute myeloid leukemia. This review analyzes and discusses how these cells adapt through redox-modulated intricate connections, via interaction of OGG1 with NFκB, which provides malignant cells with alternative molecular pathways to transform their microenvironment, enabling adjustment, promoting cell proliferation, metastasis, and evading killing by therapeutic agents. [ABSTRACT FROM AUTHOR]

Interferons (IFNs) are secreted cytokines with the ability to activate expression of IFN stimulated genes that increase resistance of cells to virus infections. Activated transcription factors in conjunction with chromatin remodelers induce epigenetic changes that reprogram IFN responses. Unexpectedly, 8-oxoguanine DNA glycosylase1 (Ogg1) knockout mice show enhanced stimuli-driven IFN expression that confers increased resistance to viral and bacterial infections and allergen challenges. Here, we tested the hypothesis that the DNA repair protein OGG1 recognizes 8-oxoguanine (8-oxoGua) in promoters modulating IFN expression. We found that functional inhibition, genetic ablation, and inactivation by post-translational modification of OGG1 significantly augment IFN-λ expression in epithelial cells infected by human respiratory syncytial virus (RSV). Mechanistically, OGG1 bound to 8-oxoGua in proximity to interferon response elements, which inhibits the IRF3/IRF7 and NF-κB/RelA DNA occupancy, while promoting the suppressor NF-κB1/p50-p50 homodimer binding to the IFN-λ2/3 promoter. In a mouse model of bronchiolitis induced by RSV infection, functional ablation of OGG1 by a small molecule inhibitor (TH5487) enhances IFN-λ production, decreases immunopathology, neutrophilia, and confers antiviral protection. These findings suggest that the ROS-generated epigenetic mark 8-oxoGua via its reader OGG1 serves as a homeostatic thresholding factor in IFN-λ expression. Pharmaceutical targeting of OGG1 activity may have clinical utility in modulating antiviral response. [ABSTRACT FROM AUTHOR]

The signaling pathways that activate Activating Transcription Factor-2(ATF-2), a sequence-specific DNA-binding protein of the bZIP family of proteins, and its downstream targets and the role of ATF-2 in carcinogenesis in comparison with other bZIP proteins is analyzed.

Summary: Chloroquines are 4‐aminoquinoline‐based drugs mainly used to treat malaria. At pharmacological concentrations, they have significant effects on tissue homeostasis, targeting diverse signaling pathways in mammalian cells. A key target pathway is autophagy, which regulates macromolecule turnover in the cell. In addition to affecting cellular metabolism and bioenergetic flow equilibrium, autophagy plays a pivotal role at the interface between inflammation and cancer progression. Chloroquines consequently have critical effects in tissue metabolic activity and importantly, in key functions of the immune system. In this article, we will review the work addressing the role of chloroquines in the homeostasis of mammalian tissue, and the potential strengths and weaknesses concerning their use in cancer therapy. [ABSTRACT FROM AUTHOR]