Context-specific effects of NOX4 inactivation in acute myeloid leukemia (AML).
J Cancer Res Clin Oncol
; 148(8): 1983-1990, 2022 Aug.
Article
em En
| MEDLINE
| ID: mdl-35348887
ABSTRACT
PURPOSE:
Oxidative stress has been linked to initiation and progression of cancer and recent studies have indicated a potential translational role regarding modulation of ROS in various cancers, including acute myeloid leukemia (AML). Detailed understanding of the complex machinery regulating ROS including its producer elements in cancer is required to define potential translational therapeutic use. Based on previous studies in acute myeloid leukemia (AML) models, we considered NADPH oxidase (NOX) family members, specifically NOX4 as a potential target in AML.METHODS:
Pharmacologic inhibition and genetic inactivation of NOX4 in murine and human models of AML were used to understand its functional role. For genetic inactivation, CRISPR-Cas9 technology was used in human AML cell lines in vitro and genetically engineered knockout mice for Nox4 were used for deletion of Nox4 in hematopoietic cells via Mx1-Cre recombinase activation.RESULTS:
Pharmacologic NOX inhibitors and CRISPR-Cas9-mediated inactivation of NOX4 and p22-phox (an essential NOX component) decreased proliferative capacity and cell competition in FLT3-ITD-positive human AML cells. In contrast, conditional deletion of Nox4 enhanced the myeloproliferative phenotype of an FLT3-ITD induced knock-in mouse model. Finally, Nox4 inactivation in normal hematopoietic stem and progenitor cells (HSPCs) caused a minor reduction in HSC numbers and reconstitution capacity.CONCLUSION:
The role of NOX4 in myeloid malignancies appears highly context-dependent and its inactivation results in either enhancing or inhibitory effects. Therefore, targeting NOX4 in FLT3-ITD positive myeloid malignancies requires additional pre-clinical assessment.Palavras-chave
Texto completo:
1
Bases de dados:
MEDLINE
Assunto principal:
Leucemia Mieloide Aguda
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NADPH Oxidase 4
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Transtornos Mieloproliferativos
Limite:
Animals
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Humans
Idioma:
En
Revista:
J Cancer Res Clin Oncol
Ano de publicação:
2022
Tipo de documento:
Article
País de afiliação:
Alemanha