@article{92f035fc04874de4947351c119a76f18,
title = "The Hematopoietic Oxidase NOX2 Regulates Self-Renewal of Leukemic Stem Cells",
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. 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 = "CEBPε, FOXC1, NF-κB, NOX2, ROS, acute myeloid leukemia, differentiation, fatty acid oxidation, glycolysis, leukemia stem cells, p22Phox, self-renewal",
author = "Biniam Adane and Haobin Ye and Nabilah Khan and Shanshan Pei and Mohammad Minhajuddin and Stevens, {Brett M.} and Jones, {Courtney L.} and Angelo D'Alessandro and Reisz, {Julie A.} and Vadym Zaberezhnyy and Maura Gasparetto and Ho, {Tzu Chieh} and Kelly, {Kathleen K.} and Myers, {Jason R.} and Ashton, {John M.} and Julie Siegenthaler and Tsutomu Kume and Campbell, {Eric L.} and Pollyea, {Daniel A.} and Becker, {Michael W.} and Jordan, {Craig T.}",
note = "Funding Information: We gratefully acknowledge our patients and their families for their participation in this study, Dr. Linda Johnson for help with histopathology analysis, and Drs. Julie Gold, Rachel H. McMahan, and Eric Pietras for providing additional mice used in some studies. We also thank Dr. Patricia Ernst for providing the MSCV-puro plasmid. C.T.J. is supported by the Nancy Carroll Allen Endowed Chair in Hematology and NIH grants R01CA166265 and R01CA200707, and B.A. is supported by Ruth L. Kirschstein Individual Predoctoral National Service Award (F31CA196330-01). C.L.J. is supported by the American Cancer Society (grant 25A5072) and the Colorado Clinical and Translational Sciences Institute (grant AEF CCTSI YR9 CO 2301425). We thank the functional genomics core at University of Colorado Anschutz Medical Campus cancer center (supported in part by grant 5P30CA046934) for providing shRNA constructs. B.A. and C.T.J. conceived and designed all experiments, analyzed and interpreted the data, and wrote the manuscript. H.Y. assisted in designing experiments and manuscript preparation. N.K. and H.Y. assisted with all experiments involving murine models and xenograft studies. S.P. performed all bioinformatics analysis. M.M. assisted with lentivirus production for primary AML studies. B.M.S. organized animal protocols and assisted with flow cytometry analysis. C.L.J. performed metabolic analysis with help from A.D. and J.A.R. V.Z. performed irradiation and murine transplantation experiments. M.G. assisted with flow cytometry. T.-C.H. performed primary AML LSC transcriptomic studies. J.R.M. and J.M.A. performed Illumina sequencing and assisted with RNA-seq analysis. T.K. K.K. and J.S. generated and provided FOXC1fl/fl mice. E.L.C. provided NOX2 KO mice. D.A.P. and M.W.B. obtained AML patient specimens. The authors declare no competing interests. Funding Information: We gratefully acknowledge our patients and their families for their participation in this study, Dr. Linda Johnson for help with histopathology analysis, and Drs. Julie Gold, Rachel H. McMahan, and Eric Pietras for providing additional mice used in some studies. We also thank Dr. Patricia Ernst for providing the MSCV-puro plasmid. C.T.J. is supported by the Nancy Carroll Allen Endowed Chair in Hematology and NIH grants R01CA166265 and R01CA200707 , and B.A. is supported by Ruth L. Kirschstein Individual Predoctoral National Service Award ( F31CA196330-01 ). C.L.J. is supported by the American Cancer Society (grant 25A5072 ) and the Colorado Clinical and Translational Sciences Institute (grant AEF CCTSI YR9 CO 2301425 ). We thank the functional genomics core at University of Colorado Anschutz Medical Campus cancer center (supported in part by grant 5P30CA046934 ) for providing shRNA constructs. Publisher Copyright: {\textcopyright} 2019 The Authors",
year = "2019",
month = apr,
day = "2",
doi = "10.1016/j.celrep.2019.03.009",
language = "English (US)",
volume = "27",
pages = "238--254.e6",
journal = "Cell Reports",
issn = "2211-1247",
publisher = "Cell Press",
number = "1",
}
