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Leukemias
Published in Pat Price, Karol Sikora, Treatment of Cancer, 2020
HCL is a rare chronic mature B-cell malignancy which presents with progressive pancytopenia, splenomegaly, infiltration of bone marrow, liver, and spleen, and circulating B-cells possessing cytoplasmic projections that resemble “hair-like” microvilli (Figure 28.19). It affects about 1 in 100,000 adults, largely males, and has unique clinical, pathological, biologic, and genetic features.9 The 2008 WHO classification recognized two subtypes, a classic (HCLc) and a variant (HCLv), which in the 2016 WHO revised version, have provisionally been placed in the category of “splenic lymphomas, unclassified.” The discovery of BRAFV600E as a driver mutation of HCLc provides important insights into the disease pathogenesis and novel treatment. The HCL genome is generally considered to be stable, with fewer than 10% of patients demonstrating recurrent chromosomal abnormalities, in particular deletion of the long arm of chromosome 7, and no copy number alterations. Genomic sequencing studies have also revealed the presence of mutations in the tumor suppressor CDKN1B gene, encoding for the cyclin-dependent kinase inhibitor p27 and in the KLF2 gene, which encodes for a transcription factor in some patients with HCLc.173
Involvement of Dopamine with Various Cancers
Published in Nira Ben-Jonathan, Dopamine, 2020
Impaired tumor blood flow, caused by structurally and functionally abnormal blood vessels, aggravates tumor hypoxia, hinders the delivery of chemotherapeutic agents, and increases resistance of tumor cells to antineoplastic drugs [54]. The third study from the above laboratory examined whether DA affected the stabilization of tumor vasculature [55]. The results showed loss of sympathetic innervation and DA in abnormal tumor blood vessels in malignant colon xenograft. DA administration normalized the morphology and improved the functions of tumor vessels by acting upon pericytes and endothelial cells. D2R activation up-regulated the expression of angiopoietin 1 in pericytes and expression of KLF2 in tumor endothelial cells. Vessel stabilization by DA also increased the concentration of 5-FU in tumor tissues. These results established a functional relationship between vascular stabilization and DA and indicated that D2R-selective agonists should be considered for treating colon cancer and other disorders in which normalization of blood vessels have therapeutic benefits.
Non-Hodgkin Lymphoma
Published in Tariq I. Mughal, Precision Haematological Cancer Medicine, 2018
Marginal zone lymphomas (MZL) share recurrent trisomies of chromosomes 3 and 18, and deletions at 6q23 (TNFAIP3). In addition, the mucosa-associated lymphoid tissue (MALT) subtype, but not the splenic MZL nor nodal MZL, have recurrent chromosomal translocations, such as t(11;18)(q21.q21), t(1;14)(p22;q32), t(14;18)(q32;q21) and t(3;14)(p14;q32) involving the AP12-MALT1, IGH-BCL10, IGH-MALT1 and IGH-FOXP1 genes, respectively; some of these genes are involved in the NFĸB pathway. Interestingly, there appears to be an association for certain translocations and specific anatomical sites, for example, t(11:18) and the stomach and t(14;18) and the lung. The splenic and nodular variants exhibit recurrent mutations affecting the NOTCH pathway and the transcription factor KLF2.
KLF2 reduces dexamethasone-induced injury to growth plate chondrocytes by inhibiting the Runx2-mediated PI3K/AKT and ERK signalling pathways
Published in Autoimmunity, 2023
Yulong Ma, Tao Peng, Xudong Yao, Chaonan Sun, Xiaowei Wang
Previous studies have shown that KLF2 is expressed and plays a regulatory role in the lung, T cells, T-reg cells, endothelial cells, monocytes and other related tissues and cells, and is related to a variety of inflammatory and pathological states [21, 22]. In addition, KLF2 is expressed in osteoblasts and primary osteoblasts [23]. Interestingly, KLF2 expression is increased in osteoblasts during osteoblast differentiation [24]. Importantly, we found that KLF2 can physically interact with Runx2. KLF2 promotes osteoblast differentiation by regulating Runx2 and the physical interaction with Runx2. Based on these results, this study found that KLF2 is a new regulatory factor involved in osteoblast differentiation, suggesting that KLF2 may be a new target for the treatment of bone diseases [10]. In this study, we found that KLF2 expression was down-regulated in the Dex-treated rat GPCs, and played a protective role in the proliferation reduction and apoptosis of chondrocytes. Furthermore, our in vivo data suggested that overexpression of KLF2alleviated Dex-induced growth retardation in rats by inhibiting GPCs.
Deciphering the genotype and phenotype of hairy cell leukemia: clues for diagnosis and treatment
Published in Expert Review of Clinical Immunology, 2019
Margot C.E. Polderdijk, Michiel Heron, Saskia Kuipers, Ger T. Rijkers
Maitre et al. [74] described many mutations that have not been associated with HCL before or at least to a very limited extent. The KDM6A mutation is located on the X chromosome, and could perhaps explain the male predominance of HCL. The mutation results in loss of function of a lysine demethylase protein, which may sensitize tumor cells to EZH2 inhibitors. The KLF2 mutation appears in 10–16% of patients. This gene is involved in inhibition of the NFκB pathway, as well as B-cell homing to lymph nodes. The mutations found are either in the zinc finger domain or nuclear localization signal, and both lead to loss of function of the protein. The exact mechanisms are unknown, but it is consistent with the NFκB activation that is reported in HCL [76]. The mutation is found also in splenic marginal zone lymphoma. U2AF1 splicing factor mutations are reported by Durham et al. [27], but only in HCLv. Similarly, these researchers found CCND3 mutations in 13% of HCLv patients, which led to loss of the PEST domain and increased expression of CCND3. Elevated levels of the related CCND1 mRNA have been found also, but it is not clear what the implications for this are [77]. The product of CCND1, cyclin D1, is sometimes used as a diagnostic marker for HCL.
The protective effects of aloperine against ox-LDL-induced endothelial dysfunction and inflammation in HUVECs
Published in Artificial Cells, Nanomedicine, and Biotechnology, 2020
Weiwei Li, Yanshu Li, Yi Zhao, Lina Ren
IL-6 and MCP-1 are proinflammatory factors that play a critical role in atherogenesis. Increased IL-6 has long been documented in atherosclerotic lesions and is secreted in response to ox-LDL exposure [9]. Additionally, IL-6 is recognized as a key contributor to atherogenesis and plasma levels of IL-6 are an independent indicator of atherosclerosis and mortality in patients with HIV [10,11]. MCP-1 drives inflammation and lesion formation by recruiting monocytes to the subendothelial space [12]. The attachment of monocytes to endothelial cells is driven by cellular adhesion molecules, including VCAM-1 and E-selectin. These adhesion molecules are strongly expressed in areas of disturbed flow such as bifurcations and curvatures. VCAM-1 and E-selectin induce monocytes to roll along and adhere to the arterial wall, at which point they can invade the intima, giving rise to the formation of foam cells and increasing intima-media thickness, inflammation, and oxidative stress [13,14]. Specific inhibition of adhesion molecules is considered an effective treatment strategy against atherosclerosis [15]. KLF2 is an important protective transcriptional factor that can mitigate the functions of endothelial cells [16]. KLF2 is upregulated at areas exposed to laminar shear stress, but in areas of disturbed flow, KLF2 expression is suppressed. Additionally, hyperlipidemic conditions inhibit KLF2 expression, thereby lowering a major natural defence mechanism against the formation of atherosclerotic plaques [17]. Rescue of KLF2 expression is able to mediate the anti-inflammatory and anti-cellular adhesion effects of montelukast against ox-LDL-induced atherogenesis [18].