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Cell Rep. 2019 Apr 2;27(1):238-254.e6. doi: 10.1016/j.celrep.2019.03.009.

The Hematopoietic Oxidase NOX2 Regulates Self-Renewal of Leukemic Stem Cells.

Author information

1
Division of Hematology, Anschutz Medical Campus, University of Colorado, Aurora, CO 80045, USA; Department of Biochemistry and Molecular Genetics, Anschutz Medical Campus, University of Colorado, Aurora, CO 80045, USA.
2
Division of Hematology, Anschutz Medical Campus, University of Colorado, Aurora, CO 80045, USA.
3
Department of Biochemistry and Molecular Genetics, Anschutz Medical Campus, University of Colorado, Aurora, CO 80045, USA.
4
Genomics Research Center, University of Rochester, NY 14642, USA.
5
Department of Pediatrics, Anschutz Medical Campus, University of Colorado, Aurora, CO 80045, USA.
6
Feinberg Cardiovascular and Renal Research Institute, Northwestern University School of Medicine, Chicago, IL 60611, USA.
7
School of Medicine, Dentistry and Biomedical Sciences, Queens University, Belfast, UK.
8
Division of Hematology, Anschutz Medical Campus, University of Colorado, Aurora, CO 80045, USA. Electronic address: craig.jordan@ucdenver.edu.

Abstract

The NADPH-dependent oxidase NOX2 is an important effector of immune cell function, and its activity has been linked to oncogenic signaling. Here, we describe a role for NOX2 in leukemia-initiating stem cell populations (LSCs). In a murine model of leukemia, suppression of NOX2 impaired core metabolism, attenuated disease development, and depleted functionally defined LSCs. Transcriptional analysis of purified LSCs revealed that deficiency of NOX2 collapses the self-renewal program and activates inflammatory and myeloid-differentiation-associated programs. Downstream of NOX2, we identified the forkhead transcription factor FOXC1 as a mediator of the phenotype. Notably, suppression of NOX2 or FOXC1 led to marked differentiation of leukemic blasts. In xenotransplantation models of primary human myeloid leukemia, suppression of either NOX2 or FOXC1 significantly attenuated disease development. Collectively, these findings position NOX2 as a critical regulator of malignant hematopoiesis and highlight the clinical potential of inhibiting NOX2 as a means to target LSCs.

KEYWORDS:

CEBPε; FOXC1; NF-κB; NOX2; ROS; acute myeloid leukemia; differentiation; fatty acid oxidation; glycolysis; leukemia stem cells; p22Phox; self-renewal

PMID:
30943405
DOI:
10.1016/j.celrep.2019.03.009
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