期刊
CELL REPORTS
卷 27, 期 1, 页码 238-+出版社
CELL PRESS
DOI: 10.1016/j.celrep.2019.03.009
关键词
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类别
资金
- Nancy Carroll Allen Endowed Chair in Hematology
- NIH [R01CA166265, R01CA200707]
- Ruth L. Kirschstein Individual Predoctoral National Service Award [F31CA196330-01]
- American Cancer Society [25A5072]
- Colorado Clinical and Translational Sciences Institute [AEF CCTSI YR9 CO 2301425]
- [5P30CA046934]
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.
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