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Context-specific effects of NOX4 inactivation in acute myeloid leukemia (AML)

Muhammed Burak Demircan1,2,3,4, Tina M Schnoeder5, Peter C Mgbecheta3

  • 1Innere Medizin II, Hämatologie und Onkologie, Jena University Hospital, Jena, Germany.

Journal of Cancer Research and Clinical Oncology
|March 29, 2022
PubMed
Abstract

Insights

Targeting NADPH oxidase 4 (NOX4) in acute myeloid leukemia (AML) showed context-dependent effects. In some cases, NOX4 inactivation inhibited cancer cell proliferation, while in others, it enhanced disease progression, necessitating further preclinical evaluation.

Area of Science:

  • Oncology
  • Molecular Biology
  • Hematology

Background:

  • Oxidative stress is implicated in cancer development and progression.
  • Reactive oxygen species (ROS) modulation is a potential therapeutic strategy in cancers like acute myeloid leukemia (AML).
  • NADPH oxidase (NOX) family members are key regulators of ROS production.

Purpose of the Study:

  • To investigate the role of NOX4, a specific NADPH oxidase family member, as a potential therapeutic target in AML.
  • To understand the complex machinery regulating ROS and its producer elements in AML.

Main Methods:

  • Utilized pharmacologic inhibition and genetic inactivation of NOX4 in murine and human AML models.
  • Employed CRISPR-Cas9 technology for in vitro genetic inactivation in human AML cell lines.
  • Generated genetically engineered knockout mice for Nox4 deletion in hematopoietic cells.

Main Results:

  • NOX4 and p22-phox inactivation decreased proliferation in FLT3-ITD-positive AML cells.
  • Conditional deletion of Nox4 exacerbated the myeloproliferative phenotype in a FLT3-ITD mouse model.
  • Inactivation of NOX4 in normal hematopoietic stem and progenitor cells (HSPCs) led to a minor reduction in HSC numbers and reconstitution capacity.

Conclusions:

  • The function of NOX4 in myeloid malignancies is highly context-dependent.
  • NOX4 inactivation can have opposing effects, either inhibiting or enhancing disease progression.
  • Targeting NOX4 in FLT3-ITD positive myeloid malignancies requires further preclinical investigation.
Keywords:
Acute myeloid leukemia (AML)CRISPR-Cas9FLT3-ITDNADPH oxidases (NOX)Nox4Oxidative stressReactive oxygen species (ROS)

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