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Deregulation of tumor suppressive ASXL1-PTEN/AKT axis in myeloid malignancies

Lei Cao1, Xianyou Xia1, Yu Kong1

  • 1Collaborative Innovation Center of Tianjin for Medical Epigenetics, Tianjin Key Laboratory of Medical Epigenetics, Key Laboratory of Immune Microenvironment and Disease (Ministry of Education), Department of Cell Biology, Tianjin Medical University, Tianjin 300070, China.

Journal of Molecular Cell Biology
|April 3, 2020
PubMed

Insights

ASXL1 mutations in myeloid malignancies disrupt PTEN gene regulation, leading to sustained AKT signaling. Targeting this pathway offers a new therapeutic strategy for patients with ASXL1 mutations.

Area of Science:

  • Epigenetics
  • Molecular Biology
  • Cancer Research

Background:

  • Mutations in epigenetic regulators like ASXL1 are common in human cancers, particularly myeloid malignancies.
  • ASXL1, in complex with BAP1, removes the H2AK119ub1 mark, a key epigenetic repressor.
  • The precise role of ASXL1 in transcriptional regulation and tumor suppression requires further elucidation.

Purpose of the Study:

  • To investigate the mechanistic link between ASXL1, epigenetic regulation, and myeloid malignancies.
  • To explore the impact of ASXL1 depletion on cellular signaling pathways.
  • To identify potential therapeutic targets for ASXL1-mutated cancers.

Main Methods:

  • Depletion of Asxl1 in murine 32D cells.
  • Analysis of PI3K/AKT signaling pathway activation.
  • Chromatin immunoprecipitation to assess ASXL1 enrichment and H2AK119 deubiquitylation at the Pten promoter.
  • Correlation analysis of ASXL1 and PTEN expression in human blood cells and myeloid malignancies.
  • Assessment of sensitivity to AKT inhibitor MK2206 in ASXL1-mutated cells.

Main Results:

  • Asxl1 depletion promotes IL3-independent growth in murine cells, linked to sustained PI3K/AKT signaling.
  • Asxl1 is essential for the transcriptional activation of Pten, a negative regulator of AKT.
  • ASXL1 is specifically required for H2AK119 deubiquitylation at the Pten promoter.
  • ASXL1 and PTEN expression are positively correlated in human blood cells; ASXL1 mutations correlate with lower PTEN levels in myeloid malignancies.
  • Malignant cells with ASXL1 alterations show increased sensitivity to the AKT inhibitor MK2206.

Conclusions:

  • ASXL1 plays a critical role in regulating Pten transcription and suppressing myeloid malignancies via the PTEN/AKT pathway.
  • ASXL1 mutations disrupt this epigenetic-PTEN-AKT axis, contributing to cancer development.
  • Targeting the AKT pathway with inhibitors like MK2206 presents a promising therapeutic approach for ASXL1-mutated myeloid malignancies.
Keywords:
AKTH2A ubiquitylationPTENPolycombtumor suppressor

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