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HDAC4 inhibition disrupts TET2 function in high-risk MDS and AML

Feiteng Huang1,2, Jie Sun2, Wei Chen3

  • 1Department of Hematology, Sir Run Run Shaw Hospital, School of Medicine, Zhejiang University, Hangzhou 310016, China.

Aging
|July 30, 2020
PubMed

Insights

Histone deacetylase inhibitors (HDACi) can reduce TET2 activity in myeloid neoplasms. Combining HDACi with TET2 agonists, like vitamin C, may improve treatment efficacy for high-risk myelodysplastic syndromes and acute myeloid leukemia.

Area of Science:

  • Epigenetics
  • Cancer Biology
  • Hematology

Background:

  • Aberrant DNA methylation and histone deacetylation are hallmarks of myeloid neoplasms, impacting tumor-suppressor genes and cell differentiation.
  • A prior study suggested antagonism between histone deacetylase inhibitors (HDACi) and DNA hypomethylating agents (HMA).

Purpose of the Study:

  • To investigate the potential pharmacodynamic antagonism between HDACi and DNA hypomethylating agents in myeloid neoplasms.
  • To elucidate the mechanism by which HDACi affect TET2 activity and explore therapeutic combinations.

Main Methods:

  • Utilized myelodysplastic syndrome (MDS)/acute myeloid leukemia (AML) cell lines and NHD13 transgenic mice.
  • Conducted RNA interference (RNAi) screening to identify key regulators of TET2.
  • Analyzed GEO datasets for prognostic correlation of HDAC4 levels in AML patients.
  • Employed an MDS-L xenograft immunodeficient mouse model with vitamin C co-treatment.

Main Results:

  • Treatment with suberoylanilide hydroxamic acid (SAHA), a pan-HDACi, decreased TET2 expression and global 5-hydroxymethylcytosine (5hmC) levels.
  • HDAC4 was identified as crucial for maintaining TET2 levels; its knockout reduced TET2 target gene expression and enhancer 5hmC enrichment.
  • Lower HDAC4 levels correlated with worse prognosis in AML patients.
  • Vitamin C co-treatment prevented SAHA-induced TET2 loss and reduced MDS-L cell engraftment.

Conclusions:

  • Pan-HDACi treatment can diminish TET2 activity, potentially through HDAC4.
  • Co-administration of TET2 agonists with pan-HDACi may counteract this diminution.
  • This strategy provides a rationale for evaluating combination therapies against high-risk MDS/AML.
Keywords:
TET2acute myeloid leukemiahistone deacetylasemyelodysplastic syndromes

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