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The deacetylases HDAC1/HDAC2 control JAK2V617F-STAT signaling through the ubiquitin ligase SIAH2

Al-Hassan M Mustafa1,2, Giuseppe Petrosino3, Marten A Fischer4

  • 1Institute of Toxicology, University Medical Center of Johannes Gutenberg University, Mainz, Germany. alabdeen@uni-mainz.de.

Signal Transduction and Targeted Therapy
|August 28, 2025
PubMed

Insights

Histone deacetylase (HDAC) inhibitors induce apoptosis in myeloproliferative neoplasm (MPN) cells by targeting HDAC1/HDAC2, which stabilizes SIAH2. This leads to JAK2V617F degradation, offering a new therapeutic strategy for MPNs.

Area of Science:

  • Oncology
  • Epigenetics
  • Molecular Biology

Background:

  • Histone deacetylases (HDACs) are epigenetic modulators crucial for biological processes, often dysregulated in cancers like myeloproliferative neoplasms (MPNs).
  • Patients with MPNs carrying the Janus kinase-2 (JAK2V617F) mutation show enhanced response to HDAC inhibitors (HDACi).
  • JAK2V617F activates Signal Transducer and Activator of Transcription (STAT) factors, promoting cell proliferation and inflammation.

Purpose of the Study:

  • To investigate the molecular mechanisms by which HDAC inhibitors (HDACi) exert superior activity in JAK2V617F-mutated MPNs.
  • To identify novel therapeutic targets within the HDAC-SIAH2-JAK2 signaling axis for MPN treatment.
  • To assess the therapeutic potential of HDAC1/HDAC2 inhibition in MPN models.

Main Methods:

  • Treatment of primary and permanent MPN cells with HDAC inhibitors (romidepsin, entinostat, MERCK60) and genetic depletion of HDAC1/HDAC2.
  • Assessment of apoptosis, growth arrest, and differentiation in MPN cells and normal hematopoietic stem cells.
  • Molecular analyses including protein stability assays, genetic knockout experiments (SIAH2), and global RNA sequencing.
  • Prognostic analysis of HDAC1 expression in acute myeloid leukemia patients.

Main Results:

  • HDAC1/HDAC2 inhibition induced apoptosis and long-term growth arrest in MPN cells, sparing normal hematopoietic stem cells.
  • HDAC1 and HDAC2 regulate SIAH2 protein stability via acetylation; SIAH2 promotes proteasomal degradation of JAK2V617F.
  • SIAH2 knockout MPN cells exhibited reduced sensitivity to HDAC inhibitors.
  • JAK-STAT signaling was identified as a key target regulated by SIAH2.
  • HDAC1 expression correlated with adverse prognosis in acute myeloid leukemia patients.

Conclusions:

  • HDAC1/HDAC2 are critical molecular targets in JAK2V617F-positive MPNs, mediating therapeutic effects of HDAC inhibitors.
  • The HDAC1/HDAC2-SIAH2-JAK2V617F axis represents a previously unappreciated regulatory pathway controlling cell proliferation and survival in MPNs.
  • Targeting HDAC1/HDAC2 offers a promising therapeutic strategy for MPNs, with potential implications for other myeloid malignancies.

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