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    Aldehyde dehydrogenase genes as prospective actionable targets in acute myeloid leukemia
    (MDPI, 2023) Dancik, Garrett M.; Varışli, Lokman; Tolan, Veysel; Vlahopoulos, Spiros
    It has been previously shown that the aldehyde dehydrogenase (ALDH) family member ALDH1A1 has a significant association with acute myeloid leukemia (AML) patient risk group classification and that AML cells lacking ALDH1A1 expression can be readily killed via chemotherapy. In the past, however, a redundancy between the activities of subgroup members of the ALDH family has hampered the search for conclusive evidence to address the role of specific ALDH genes. Here, we describe the bioinformatics evaluation of all nineteen member genes of the ALDH family as prospective actionable targets for the development of methods aimed to improve AML treatment. We implicate ALDH1A1 in the development of recurrent AML, and we show that from the nineteen members of the ALDH family, ALDH1A1 and ALDH2 have the strongest association with AML patient risk group classification. Furthermore, we discover that the sum of the expression values for RNA from the genes, ALDH1A1 and ALDH2, has a stronger association with AML patient risk group classification and survival than either one gene alone does. In conclusion, we identify ALDH1A1 and ALDH2 as prospective actionable targets for the treatment of AML in high-risk patients. Substances that inhibit both enzymatic activities constitute potentially effective pharmaceutics.
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    Critical roles of SRC-3 in the development and progression of breast cancer, rendering it a prospective clinical target
    (MDPI, 31.10.2023) Varışli, Lokman; Dancik, Garrett M.; Tolan, Veysel; Vlahopoulos, Spiros
    Breast cancer (BCa) is the most frequently diagnosed malignant tumor in women and is also one of the leading causes of cancer-related death. Most breast tumors are hormone-dependent and estrogen signaling plays a critical role in promoting the survival and malignant behaviors of these cells. Estrogen signaling involves ligand-activated cytoplasmic estrogen receptors that translocate to the nucleus with various co-regulators, such as steroid receptor co-activator (SRC) family members, and bind to the promoters of target genes and regulate their expression. SRC-3 is a member of this family that interacts with, and enhances, the transcriptional activity of the ligand activated estrogen receptor. Although SRC-3 has important roles in normal homeostasis and developmental processes, it has been shown to be amplified and overexpressed in breast cancer and to promote malignancy. The malignancy-promoting potential of SRC-3 is diverse and involves both promoting malignant behavior of tumor cells and creating a tumor microenvironment that has an immunosuppressive phenotype. SRC-3 also inhibits the recruitment of tumor-infiltrating lymphocytes with effector function and promotes stemness. Furthermore, SRC-3 is also involved in the development of resistance to hormone therapy and immunotherapy during breast cancer treatment. The versatility of SRC-3 in promoting breast cancer malignancy in this way makes it a good target, and methodical targeting of SRC-3 probably will be important for the success of breast cancer treatment.
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    Editorial: Acute leukemias: molecular characterization, leukemia-initiating cells, and influence of the microenvironment
    (Frontiers, 2023) Dancik, Garrett M.; Varışli, Lokman; Voutsas, Ioannis F.; Vlahopoulos, Spiros
    Acute leukemias remain a challenge, in spite of improvements in diagnosis and treatment. Fully establishing the depth and extent of the relative impact of the molecular mechanisms of disease progression and the pathways to recurrent disease will require decades of research, until our comprehension enables the routine development of simple and effective cures. This special issue was aimed to address progress in the characterization of the molecular basis of acute leukemias and to explore potential links with disease course.
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    Editorial: Acute leukemias: molecular characterization, leukemia-initiating cells, and influence of the microenvironment, volume II
    (Frontiers, 06.01.2025) Varışli, Lokman; Dancik, Garrett M.; Copland, John A.; Vlahopoulos, Spiros A.
    Acute leukemia is a wide group of hematologic malignancies that arise from leukemiainitiating cells (LICs), also known as leukemic stem cells (LSCs), which originate from transformed hematopoietic stem cells (HSCs) in the bone marrow. Leukemic cells accumulate various genetic and epigenetic defects, both inherited from the LICs they originate from and acquired later. Genetic defects in leukemic cells determine their biological behavior and, as expected, affect the prognosis of the disease and its response to treatment. Therefore, molecular characterization of the disease is important for all stages of the disease, such as predicting prognosis, determining the treatment approach, and evaluating the possibility of recurrence. In this context, a better understanding of the molecular mechanisms of acute leukemia will enable the emergence of simpler and more effective treatment approaches and increase the rate of treated patients.
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    The Molecular context of oxidant stress response in cancer establishes ALDH1A1 as a critical target: What this means for acute myeloid leukemia
    (MDPI, 2023) Dancik, Garrett M.; Varışli, Lokman; Vlahopoulos, Spiros A.
    The protein family of aldehyde dehydrogenases (ALDH) encompasses nineteen members. The ALDH1 subfamily consists of enzymes with similar activity, having the capacity to neutralize lipid peroxidation products and to generate retinoic acid; however, only ALDH1A1 emerges as a significant risk factor in acute myeloid leukemia. Not only is the gene ALDH1A1 on average significantly overexpressed in the poor prognosis group at the RNA level, but its protein product, ALDH1A1 protects acute myeloid leukemia cells from lipid peroxidation byproducts. This capacity to protect cells can be ascribed to the stability of the enzyme under conditions of oxidant stress. The capacity to protect cells is evident both in vitro, as well as in mouse xenografts of those cells, shielding cells effectively from a number of potent antineoplastic agents. However, the role of ALDH1A1 in acute myeloid leukemia has been unclear in the past due to evidence that normal cells often have higher aldehyde dehydrogenase activity than leukemic cells. This being true, ALDH1A1 RNA expression is significantly associated with poor prognosis. It is hence imperative that ALDH1A1 is methodically targeted, particularly for the acute myeloid leukemia patients of the poor prognosis risk group that overexpress ALDH1A1 RNA.
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    OGG1 as an epigenetic reader affects NF?B: What this means for cancer
    (MDPI, 2024) Vlahopoulos, Spiros; Pan, Lang; Varışli, Lokman; Dancik, Garrett M.; Karantanos, Theodoros; Boldogh, Istvan
    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.