The NADPH oxidase NOX2 is a marker of adverse prognosis involved in chemoresistance of acute myeloid leukemias

Abstract

Resistance to chemotherapeutic drugs is a major cause of treatment failure in Acute Myeloid Leukemias (AML). To better characterize the mechanisms of chemoresistance, we first identified genes whose expression is dysregulated in AML cells resistant to daunorubicin (DNR) or cytarabine (Ara-C), the main drugs used for the induction therapy. The genes found activated are mostly linked to immune signaling and inflammation. Among them, we identified a strong up-regulation of the NOX2 NAPDH oxidase subunit genes (CYBB, CYBA, NCF1, NCF2, NCF4 and RAC2). The ensuing increase in NADPH oxidase expression and ROS production, which is particularly strong in DNR-resistant cells, participates in the acquisition and/or maintenance of resistance to DNR. Gp91phox (CYBB-encoded Nox2 catalytic sub-unit), was found more expressed and active in leukemic cells from the FAB M4/M5 subtypes patients compared to FAB M0-M2 ones. Moreover, its expression was increased at the surface of patient’s chemotherapy resistant AML cells. Using a gene expression-based score we finally demonstrate that high NOX2 subunit genes expression is a marker of adverse prognosis in AML patients. The prognosis NOX score we defined is independent of the cytogenetic-based risk classification, FAB subtype, FLT3/NPM1 mutational status and age.

Low NETosis Induced in Anaplasma phagocytophilum-Infected Cells

“…Based on this network ( Figure 1 A), CD14, ITGB2, CYBB, and NCF1, have higher scores of interactions. Given the role of ITGB2 in the adhesion and transmigration of neutrophils [ 19 , 20 ] and that CYBB and NCF1 genes encode NADPH oxidase 2 (NOX2) subunits [ 21 ], we hypothesized that CD14 + neutrophils could induce NETosis through NOX2. To achieve this hypothesis and understand gene product attributes, we used gene ontology.…”

“…Interestingly, our data showed a significant upregulation of NOX2 subunits NCF1 and CYBB in infected cells, but these data contrast with previously published evidence that reported that ROS phagocytosis is inhibited in A. phagocytophilum -infected cells. ROS release is not only involved in phagocytosis, but many biological processes like NETosis require ROS secretion [ 21 ]. Furthermore, we found an increase in many molecules involved in TLR4 signaling, such as MAPK1, MAP2K1, RPS6KA3, and RPS6KA1, in A. phagocytophilum -infected granulocytes by protein–protein interaction analyses.…”

Global disease burden and trends of leukemia attributable to occupational risk from 1990 to 2019: An observational trend study

“…For example, the World Health Organization (WHO) classification ( 2 , 39 ), recognized as a standard for disease diagnosis and public health monitoring worldwide, has been revised from the primary to the 5 th edition during the past 60 years ( 2 ). French-American-British (FAB) classification ( 40 ) and MICM classification (Morphology, Immunology, Cytogenetics, and Molecular) classification ( 41 ). Meanwhile, the diagnostic criteria for leukemia have also changed ( 42 , 43 ).…”

NOX2: a determinant of acute myeloid leukemia survival

“…In this issue of Haematologica , Paolillo et al investigate mechanisms of chemotherapy resistance in acute myeloid leukemia (AML). 1 While AML therapy is evolving rapidly, many patients will receive conventional induction chemotherapy which consists of a 7-day continual infusion of cytarabine accompanied by infusions of an anthracycline, such as daunorubicin, on the first 3 days of treatment. Many patients receiving this therapy will respond but it is common for patients to develop disease recurrence and succumb to this disease.…”

“… Graphical representation of the key findings of Paolillo et al 1 (A) Elevated levels of NADPH oxidase 2 (NOX2) promote chemotherapy resistance in acute myeloid leukemia (AML) through increased production of reactive oxygen species. (B) A high NOX2 score predicts poor outcomes for AML patients.…”