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

• Published in: Cell reports (Cambridge) Vol. 27; no. 1; pp. 238 - 254.e6
• Main Authors: Adane, Biniam, Ye, Haobin, Khan, Nabilah, Pei, Shanshan, Minhajuddin, Mohammad, Stevens, Brett M., Jones, Courtney L., D’Alessandro, Angelo, Reisz, Julie A., Zaberezhnyy, Vadym, Gasparetto, Maura, Ho, Tzu-Chieh, Kelly, Kathleen K., Myers, Jason R., Ashton, John M., Siegenthaler, Julie, Kume, Tsutomu, Campbell, Eric L., Pollyea, Daniel A., Becker, Michael W., Jordan, Craig T.
• Format: Journal Article
• Language: English
• Published: United States Elsevier Inc 02.04.2019; Elsevier
• Subjects: acute myeloid leukemia; Animals; CEBPε; Cell Self Renewal; Cells, Cultured; differentiation; fatty acid oxidation; Female; Forkhead Transcription Factors - genetics; Forkhead Transcription Factors - metabolism; FOXC1; glycolysis; HEK293 Cells; Humans; Leukemia - blood; Leukemia - genetics; Leukemia - metabolism; leukemia stem cells; Leukopoiesis; Mice; Mice, Inbred C57BL; Myeloid Progenitor Cells - cytology; Myeloid Progenitor Cells - metabolism; Myeloid Progenitor Cells - pathology; NADPH Oxidase 2 - genetics; NADPH Oxidase 2 - metabolism; NF-κB; NOX2; p22Phox; ROS; self-renewal; NF-κB; FOXC1; leukemia stem cells; differentiation; p22Phox; acute myeloid leukemia; CEBPε; glycolysis; ROS; fatty acid oxidation; self-renewal; NOX2
• ISSN: 2211-1247; 2211-1247
• DOI: 10.1016/j.celrep.2019.03.009

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. [Display omitted] •Depletion of NOX2 reduces basal ROS levels and impairs core metabolism•NOX2 regulates self-renewal- and differentiation-associated transcriptional programs•Downstream of NOX2, FOXC1 controls part of the differentiation program•Depletion of FOXC1 or NOX2 impairs leukemogenesis in murine models and xenografts 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.