The Hematopoietic Oxidase NOX2 Regulates Self-Renewal of Leukemic Stem Cells
Biniam Adane,
Haobin Ye,
Nabilah Khan,
Shanshan Pei,
Mohammad Minhajuddin,
Brett M. Stevens,
Courtney L. Jones,
Angelo D’Alessandro,
Julie A. Reisz,
Vadym Zaberezhnyy,
Maura Gasparetto,
Tzu-Chieh Ho,
Kathleen K. Kelly,
Jason R. Myers,
John M. Ashton,
Julie Siegenthaler,
Tsutomu Kume,
Eric L. Campbell,
Daniel A. Pollyea,
Michael W. Becker,
Craig T. Jordan
Affiliations
Biniam Adane
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
Haobin Ye
Division of Hematology, Anschutz Medical Campus, University of Colorado, Aurora, CO 80045, USA
Nabilah Khan
Division of Hematology, Anschutz Medical Campus, University of Colorado, Aurora, CO 80045, USA
Shanshan Pei
Division of Hematology, Anschutz Medical Campus, University of Colorado, Aurora, CO 80045, USA
Mohammad Minhajuddin
Division of Hematology, Anschutz Medical Campus, University of Colorado, Aurora, CO 80045, USA
Brett M. Stevens
Division of Hematology, Anschutz Medical Campus, University of Colorado, Aurora, CO 80045, USA
Courtney L. Jones
Division of Hematology, Anschutz Medical Campus, University of Colorado, Aurora, CO 80045, USA
Angelo D’Alessandro
Department of Biochemistry and Molecular Genetics, Anschutz Medical Campus, University of Colorado, Aurora, CO 80045, USA
Julie A. Reisz
Department of Biochemistry and Molecular Genetics, Anschutz Medical Campus, University of Colorado, Aurora, CO 80045, USA
Vadym Zaberezhnyy
Department of Biochemistry and Molecular Genetics, Anschutz Medical Campus, University of Colorado, Aurora, CO 80045, USA
Maura Gasparetto
Division of Hematology, Anschutz Medical Campus, University of Colorado, Aurora, CO 80045, USA
Tzu-Chieh Ho
Genomics Research Center, University of Rochester, NY 14642, USA
Kathleen K. Kelly
Department of Pediatrics, Anschutz Medical Campus, University of Colorado, Aurora, CO 80045, USA
Jason R. Myers
Genomics Research Center, University of Rochester, NY 14642, USA
John M. Ashton
Genomics Research Center, University of Rochester, NY 14642, USA
Julie Siegenthaler
Department of Pediatrics, Anschutz Medical Campus, University of Colorado, Aurora, CO 80045, USA
Tsutomu Kume
Feinberg Cardiovascular and Renal Research Institute, Northwestern University School of Medicine, Chicago, IL 60611, USA
Eric L. Campbell
School of Medicine, Dentistry and Biomedical Sciences, Queens University, Belfast, UK
Daniel A. Pollyea
Division of Hematology, Anschutz Medical Campus, University of Colorado, Aurora, CO 80045, USA
Michael W. Becker
Genomics Research Center, University of Rochester, NY 14642, USA
Craig T. Jordan
Division of Hematology, Anschutz Medical Campus, University of Colorado, Aurora, CO 80045, USA; Corresponding author
Summary: 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. : The NADPH-dependent oxidase NOX2 is important for normal myeloid cell function. Adane et al. show that NOX2 is expressed in leukemic stem cells, where it regulates the balance of myeloid differentiation and self-renewal. Deficiency of NOX2 altered core metabolism, exacerbated inflammatory signaling, and limited in vivo disease development. Keywords: acute myeloid leukemia, leukemia stem cells, differentiation, self-renewal, glycolysis, fatty acid oxidation, NOX2, p22Phox, ROS, FOXC1, CEBPε, NF-κB
