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- Aydin, Ebru
(författare)
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Targeting NOX2 in cancer
- 2018
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Doktorsavhandling (övrigt vetenskapligt/konstnärligt)abstract
- Reactive oxygen species (ROS) are short-lived, toxic derivatives of oxygen that are produced during mitochondrial respiration and by NADPH oxidases (NOX). By enzymatically generating ROS, the myeloid cell NOX2 plays a critical role in defense against bacteria and other microorganisms. The NOX2-derived ROS have also been ascribed immunosuppressive properties and may damage DNA to induce mutagenesis, but details regarding the role of NOX2 and ROS for the initiation and progression of cancer are partly unexplored. This thesis work utilized genetic and pharmacological tools including transgenic mice, genetically modified cells and pharmacological NOX2 inhibitors to further define the role of NOX2 in cancer. The results presented in paper I implied that a NOX2 inhibitor, histamine dihydrochloride (HDC), promotes the development of monocyte-derived, antigen-presenting dendritic cells to control the in vivo growth of a murine lymphoma (EL-4). Paper II was designed to elucidate the impact of NOX2 on the process of metastasis. The results suggested that extracellularly released NOX2-derived ROS from myeloid cells may dampen natural killer (NK) cell-mediated defense against murine melanoma cells to promote hematogenous metastasis. Paper III aimed at defining the role of NOX2 in a mouse model of chronic myeloid leukemia (CML). It was observed that genetic ablation of NOX2 delayed the in vivo expansion of leukemic cells carrying the BCR-ABL1 mutation. In paper IV, it is shown that genetic and pharmacological inhibition of NOX2 delayed the development of myeloproliferation in a murine model of Kras-induced myeloid leukemia and, also, that inhibition of NOX2 function may confer protection against oxidative stress and DNA damage in cells of the leukemic clone. In summary, these studies identify NOX2 as a conceivable target in cancer therapy.
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| 2. |
- Bernson, Elin, 1987, et al.
(författare)
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Cytomegalovirus Serostatus Affects Autoreactive NK Cells and Outcomes of IL2-Based Immunotherapy in Acute Myeloid Leukemia
- 2018
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Ingår i: Cancer Immunology Research. - : American Association for Cancer Research (AACR). - 2326-6066 .- 2326-6074. ; 6:9, s. 1110-1119
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Tidskriftsartikel (refereegranskat)abstract
- Human cytomegalovirus (CMV) infection is reported to promote NK cell differentiation and education. The CMV-induced generation of highly differentiated adaptive-like NK cells has been proposed to affect favorably on the maintenance of remission in patients with acute myeloid leukemia (AML) after allogeneic stem cell transplantation (allo-SCT). The impact of CMV infection and adaptive-like NK cells on relapse and survival of patients with AML not receiving allo-SCT remains unknown. We assayed CMV IgG serostatus to determine past CMV infection in 81 nontransplanted AML patients who were receiving relapse-prevention immunotherapy comprising histamine dihydrochloride and low-dose interleukin-2 (HDC/IL2; NCT01347996). CMV seropositivity correlated negatively with leukemia-free and overall survival of patients receiving HDC/IL2, but did not correlate with outcomes in a contemporary control cohort. Analysis of outcome after stratification of patients based on concordant or discordant killer immunoglobulin-like receptor (KIR) and HLA genotypes implied that the negative impact of CMV seropositivity was restricted to patients lacking a ligand to inhibitory KIRs (iKIR). Previous CMV infection was also associated with fewer NK cells expressing only nonself iKIRs (NS-iKIR). We propose that CMV-driven NK cell education depletes the population of NS-iKIR NK cells, which in turn reduces the clinical benefit of relapse-preventive immunotherapy in AML.
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| 3. |
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| 4. |
- Kiffin, Roberta, et al.
(författare)
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Anti-Leukemic Properties of Histamine in Monocytic Leukemia: The Role of NOX2
- 2018
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Ingår i: Frontiers in Oncology. - : Frontiers Media SA. - 2234-943X. ; 8
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Tidskriftsartikel (refereegranskat)abstract
- In patients with acute myeloid leukemia (AML), treatment with histamine dihydrochloride (HDC) and low-dose IL-2 (HDC/ IL-2) in the post-chemotherapy phase has been shown to reduce the incidence of leukemic relapse. The clinical benefit of HDC/ IL-2 is pronounced in monocytic forms of AML, where the leukemic cells express histamine type 2 receptors (H2R) and the NAPDH oxidase-2 (NOX2). HDC ligates to H(2)Rs to inhibit NOX2-derived formation of reactive oxygen species, but details regarding the anti-leukemic actions of HDC remain to be elucidated. Here, we report that human NOX2(+) myelomonocytic/monocytic AML cell lines showed increased expression of maturation markers along with reduced leukemic cell proliferation after exposure to HDC in vitro. These effects of HDC were absent in corresponding leukemic cells genetically depleted of NOX2 (NOX2(-/-)). We also observed that exposure to HDC altered the expression of genes involved in differentiation and cell cycle progression in AML cells and that these effects required the presence of NOX2. HDC promoted the differentiation also of primary monocytic, but not non-monocytic, AML cells in vitro. In a xenograft model, immunodeficient NOG mice were inoculated with wild-type or NOX2(-/-) human monocytic AML cells and treated with HDC in vivo. The administration of HDC reduced the in vivo expansion of NOX2(+/+), but not of NOX2(-/-) human monocytic AML cells. We propose that NOX2 may be a conceivable target in the treatment of monocytic AML.
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