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Flow Cytometric Analysis of Mitochondrial Reactive Oxygen Species in Murine Hematopoietic Stem and Progenitor Cells and MLL-AF9 Driven Leukemia
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Flow Cytometric Analysis of Mitochondrial Reactive Oxygen Species in Murine Hematopoietic Stem and Progenitor Cells and MLL-AF9 Driven Leukemia

Published on: September 5, 2019

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Reactive oxygen species regulate the differentiation of acute promyelocytic leukemia cells through HMGB1-mediated

Liangchun Yang1, Wenwen Chai2, Yanping Wang1

  • 1Department of Pediatrics, Xiangya Hospital, Central South University Changsha, Hunan 410008, People's Republic of China.

American Journal of Cancer Research
|May 15, 2015
PubMed

Insights

Reactive oxygen species (ROS) and high-mobility group box 1 (HMGB1) are crucial for acute promyelocytic leukemia (APL) cell differentiation. HMGB1, regulated by ROS, promotes PML-RARα degradation and may be a therapeutic target for APL.

Area of Science:

  • Hematology
  • Molecular Biology
  • Cell Biology

Background:

  • Acute promyelocytic leukemia (APL) is characterized by blocked granulocyte differentiation.
  • The PML-RARα oncoprotein drives APL and is degraded during all-trans retinoic acid (ATRA) treatment.
  • Understanding the molecular mechanisms of APL differentiation is critical for therapeutic development.

Purpose of the Study:

  • To investigate the roles of reactive oxygen species (ROS) and high-mobility group box 1 (HMGB1) in ATRA-induced APL cell differentiation.
  • To elucidate the molecular pathways involving ROS, HMGB1, and PML-RARα degradation.

Main Methods:

  • Utilized the APL cell line NB4 and treated with ATRA.
  • Manipulated ROS levels using N-acetylcysteine (NAC) and superoxide dismutase-1 (SOD1) RNA interference (RNAi).
  • Assessed HMGB1 levels, autophagy, PML-RARα degradation, and p62/SQSTM1 interactions.

Main Results:

  • Down-regulation of ROS inhibited NB4 cell differentiation, while over-expression enhanced it.
  • HMGB1 was essential for ROS-mediated differentiation and promoted ATRA-induced autophagy and PML-RARα degradation.
  • ATRA increased ROS, enhanced autophagic flux, and promoted HMGB1 translocation, which facilitated PML-RARα degradation via p62/SQSTM1 interactions.

Conclusions:

  • HMGB1 is an essential regulator of ROS-induced APL cell differentiation.
  • The interplay between ROS, HMGB1, autophagy, and p62/SQSTM1 is vital for PML-RARα degradation.
  • HMGB1 represents a potential therapeutic target for APL treatment.
Keywords:
HMGB1ROSautophagycell differentiation

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