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

被引：65

作者：

Adane, Biniam ^{[1
,2
,7
]}

Ye, Haobin ^{[1
]}

Khan, Nabilah ^{[1
]}

Pei, Shanshan ^{[1
]}

Minhajuddin, Mohammad ^{[1
]}

Stevens, Brett M. ^{[1
]}

Jones, Courtney L. ^{[1
]}

D'Alessandro, Angelo ^{[2
]}

Reisz, Julie A. ^{[2
]}

Zaberezhnyy, Vadym ^{[2
]}

Gasparetto, Maura ^{[1
]}

Ho, Tzu-Chieh ^{[4
]}

Kelly, Kathleen K. ^{[3
]}

Myers, Jason R. ^{[4
]}

Ashton, John M. ^{[4
]}

Siegenthaler, Julie ^{[3
]}

Kume, Tsutomu ^{[6
]}

Campbell, Eric L. ^{[5
]}

Pollyea, Daniel A. ^{[1
]}

Becker, Michael W. ^{[4
]}

Jordan, Craig T. ^{[1
]}

机构：

[1] Univ Colorado, Div Hematol, Anschutz Med Campus, Aurora, CO 80045 USA

[2] Univ Colorado, Dept Biochem & Mol Genet, Anschutz Med Campus, Aurora, CO 80045 USA

[3] Univ Colorado, Dept Pediat, Anschutz Med Campus, Aurora, CO 80045 USA

[4] Univ Rochester, Genom Res Ctr, Rochester, NY 14642 USA

[5] Queens Univ, Sch Med Dent & Biomed Sci, Belfast, Antrim, North Ireland

[6] Northwestern Univ, Sch Med, Weinberg Cardiovasc & Renal Res Inst, Chicago, IL 60611 USA

[7] Dana Farber Canc Inst, Dept Pediat Oncol, Boston, MA 02215 USA

来源：

CELL REPORTS | 2019年 / 27卷 / 01期

关键词：

CHRONIC GRANULOMATOUS-DISEASE; NADPH OXIDASE; PROMOTES PROLIFERATION; MURINE MODEL; FOXC1; ROS; PROGENITORS; QUIESCENCE; NICHE; DEFICIENCY;

D O I：

10.1016/j.celrep.2019.03.009

中图分类号：

Q2 [细胞生物学];

学科分类号：

071009 ; 090102 ;

摘要：

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.

引用

页码：238 / +

页数：23

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