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 & 1 others Craig T. Jordan*

*Corresponding author for this work

Research output: Contribution to journalArticle

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.

Original languageEnglish (US)
Pages (from-to)238-254.e6
JournalCell reports
Volume27
Issue number1
DOIs
StatePublished - Apr 2 2019

Fingerprint

Stem cells
Oxidoreductases
NADPH Oxidase
NADP
Metabolism
Leukemia
Stem Cells
Forkhead Transcription Factors
Heterologous Transplantation
Myeloid Leukemia
Hematopoiesis
Myeloid Cells
Phenotype
Population
Cell Self Renewal

Keywords

  • CEBPε
  • FOXC1
  • NF-κB
  • NOX2
  • ROS
  • acute myeloid leukemia
  • differentiation
  • fatty acid oxidation
  • glycolysis
  • leukemia stem cells
  • p22Phox
  • self-renewal

ASJC Scopus subject areas

  • Biochemistry, Genetics and Molecular Biology(all)

Cite this

Adane, B., Ye, H., Khan, N., Pei, S., Minhajuddin, M., Stevens, B. M., ... Jordan, C. T. (2019). The Hematopoietic Oxidase NOX2 Regulates Self-Renewal of Leukemic Stem Cells. Cell reports, 27(1), 238-254.e6. https://doi.org/10.1016/j.celrep.2019.03.009
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. / The Hematopoietic Oxidase NOX2 Regulates Self-Renewal of Leukemic Stem Cells. In: Cell reports. 2019 ; Vol. 27, No. 1. pp. 238-254.e6.
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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.",
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Adane, B, Ye, H, Khan, N, Pei, S, Minhajuddin, M, Stevens, BM, Jones, CL, D'Alessandro, A, Reisz, JA, Zaberezhnyy, V, Gasparetto, M, Ho, TC, Kelly, KK, Myers, JR, Ashton, JM, Siegenthaler, J, Kume, T, Campbell, EL, Pollyea, DA, Becker, MW & Jordan, CT 2019, 'The Hematopoietic Oxidase NOX2 Regulates Self-Renewal of Leukemic Stem Cells', Cell reports, vol. 27, no. 1, pp. 238-254.e6. https://doi.org/10.1016/j.celrep.2019.03.009

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

In: Cell reports, Vol. 27, No. 1, 02.04.2019, p. 238-254.e6.

Research output: Contribution to journalArticle

TY - JOUR

T1 - The Hematopoietic Oxidase NOX2 Regulates Self-Renewal of Leukemic Stem Cells

AU - Adane, Biniam

AU - Ye, Haobin

AU - Khan, Nabilah

AU - Pei, Shanshan

AU - Minhajuddin, Mohammad

AU - Stevens, Brett M.

AU - Jones, Courtney L.

AU - D'Alessandro, Angelo

AU - Reisz, Julie A.

AU - Zaberezhnyy, Vadym

AU - Gasparetto, Maura

AU - Ho, Tzu Chieh

AU - Kelly, Kathleen K.

AU - Myers, Jason R.

AU - Ashton, John M.

AU - Siegenthaler, Julie

AU - Kume, Tsutomu

AU - Campbell, Eric L.

AU - Pollyea, Daniel A.

AU - Becker, Michael W.

AU - Jordan, Craig T.

PY - 2019/4/2

Y1 - 2019/4/2

N2 - 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.

AB - 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.

KW - CEBPε

KW - FOXC1

KW - NF-κB

KW - NOX2

KW - ROS

KW - acute myeloid leukemia

KW - differentiation

KW - fatty acid oxidation

KW - glycolysis

KW - leukemia stem cells

KW - p22Phox

KW - self-renewal

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Adane B, Ye H, Khan N, Pei S, Minhajuddin M, Stevens BM et al. The Hematopoietic Oxidase NOX2 Regulates Self-Renewal of Leukemic Stem Cells. Cell reports. 2019 Apr 2;27(1):238-254.e6. https://doi.org/10.1016/j.celrep.2019.03.009