NADPH Oxidases Are Important Regulators of Growth and Migration in Myeloid Neoplasms

Autor:	Margret S. Fernandes, Mamatha M. Reddy, James D. Griffin, Martin Sattler, Ravi Salgia, Ross L. Levine
Rok vydání:	2009
Předmět:	Myeloid Cell growth Immunology Myeloid leukemia NOX4 Cell Biology Hematology Biology medicine.disease Biochemistry medicine.anatomical_structure Myeloproliferative Disorders medicine Cancer research Dual Oxidases Tyrosine kinase Chronic myelogenous leukemia
Zdroj:	Blood. 114:2190-2190
ISSN:	1528-0020 0006-4971
DOI:	10.1182/blood.v114.22.2190.2190
Popis:	Abstract 2190 Poster Board II-167 Myeloid neoplasms are frequently associated with transforming tyrosine kinase oncogenes, including BCR-ABL in chronic myelogenous leukemia (CML), JAK2V617F in myeloproliferative disorders and FLT3.ITD in acute myeloid leukemia (AML). Cells transformed by tyrosine kinase oncogenes have been found to display increased levels of intracellular reactive oxygen species (ROS). Elevated ROS levels have been implicated in genomic instability through oxidative DNA damage, but also regulate cellular functions through redox-sensitive proteins. The majority of intracellular ROS in non-phagocytic cells are produced within the mitochondria. Nevertheless, recent studies indicate a role for NADPH oxidases (NOX) in transformation. There are five NOX genes (NOX1-5) and two genes encoding the related dual oxidases (DUOX1-2) in humans. We asked whether NOXs alter cell growth, migration and ROS production in hematologic malignancies transformed by tyrosine kinase oncogenes. Real-time PCR analysis in patient-derived cell lines KU812 (BCR-ABL), HEL (JAK2V617F) and Molm13 (FLT3.ITD), showed expression of NOX2, NOX4, and NOX5. Murine cells are readily transformed by BCR-ABL, JAK2V617F and FLT3.ITD, even though the gene for NOX5 is absent in mice. Therefore, we targeted NOX2 and NOX4 in KU812, HEL and Molm13 cells using lentiviral-based shRNAs. In addition, we also performed knockdown of p22phox, a common subunit that is required for stability and functioning of NOX1-4, thus also controlling for functional redundancy between the NOX genes. Interestingly, we found that p22phox knockdown reduced cell growth by 16.0-32.0% in KU812, 27.3-50.9% in HEL, and 31.3-54.2% in Molm13 cells (p Disclosures: No relevant conflicts of interest to declare.
Databáze:	OpenAIRE
Externí odkaz:	https://explore.openaire.eu/search/publication?articleId=doi_________::e5eee2887918129563b0fb65d2d4d0bf https://doi.org/10.1182/blood.v114.22.2190.2190 Zobrazit plný text záznamu