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Leukemogenic Chromatin Alterations Promote AML Leukemia Stem Cells via a KDM4C-ALKBH5-AXL Signaling Axis

Jiazhen Wang1, Yicun Li2, Peipei Wang1

  • 1The State Key Laboratory Breeding Base of Basic Science of Stomatology & Key Laboratory of Oral Biomedicine Ministry of Education, School & Hospital of Stomatology, Wuhan University, Wuhan, China; Frontier Science Center for Immunology and Metabolism, Medical Research Institute, School of Medicine, Wuhan University, Wuhan, China.

Cell Stem Cell
|May 14, 2020
PubMed

Insights

The m6A demethylase ALKBH5 is crucial for leukemia stem cell function in acute myeloid leukemia (AML). Its expression is controlled by chromatin changes, offering a potential therapeutic target for AML.

Area of Science:

  • Epigenetics
  • Molecular Biology
  • Cancer Research

Background:

  • N6-methyladenosine (m6A) is a key mRNA modification influencing cellular processes.
  • m6A modifiers regulate this reversible modification, but their regulatory mechanisms are unclear.
  • Understanding m6A modifier regulation is vital for comprehending cellular functions and diseases.

Purpose of the Study:

  • To investigate the regulation of m6A demethylase ALKBH5 during leukemogenesis.
  • To determine the role of ALKBH5 in acute myeloid leukemia (AML) and normal hematopoiesis.
  • To elucidate the mechanistic link between chromatin state and ALKBH5 expression.

Main Methods:

  • Analysis of chromatin state alterations during AML.
  • Investigating the role of KDM4C in regulating ALKBH5 expression.
  • Assessing the impact of ALKBH5 on leukemia stem cell (LSC) function and normal hematopoiesis.
  • Studying the effect of ALKBH5 on AXL mRNA stability via m6A modification.

Main Results:

  • ALKBH5 expression is regulated by chromatin state changes during AML development.
  • KDM4C enhances ALKBH5 expression by increasing chromatin accessibility and reducing H3K9me3.
  • ALKBH5 is essential for LSC function but not for normal hematopoiesis.
  • ALKBH5 influences AXL mRNA stability in an m6A-dependent manner.

Conclusions:

  • Chromatin state dynamics are linked to the expression regulation of m6A modifiers.
  • ALKBH5 plays a critical and selective role in AML by maintaining LSC function.
  • ALKBH5 represents a potential therapeutic target for specifically targeting LSCs in AML.
Keywords:
ALKBH5N(6)-methyladenosineacute myeloid leukemiachromatin accessibilityhematopoiesisleukemia stem cell

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