KDM6 and KDM4 histone lysine demethylases emerge as molecular therapeutic targets in human acute myeloid leukemia. Academic Article uri icon

Overview

abstract

  • Acute myeloid leukemia (AML) remains an aggressive hematopoietic malignancy that is caused by proliferation of immature myeloid cells and is frequently characterized by perturbations in chromatin-modifying enzymes. Emerging evidence indicates that histone demethylases play a role in tumorigenesis. However, due to the complexity of this enormous family of histone-modifying enzymes, substrate redundancy, and context-specific roles, the contribution of each member remains ambiguous and targeting them remains challenging. Here, we analyzed expression of histone-3-lysine (H3K) demethylases and their cognate substrates in a cohort of de novo AML patients, which demonstrated that the expression of H3K27Me3/2-demethylases and selected members of H3K9Me3/2/1-demethylases are significantly increased in AML. KDM6 upregulation is associated with a global decrease in H3K27Me3 level. Importantly, our data show that pharmacological inhibition of H3K27Me3/2-demethylases or H3K9Me3/2-demethylases, either alone or in combination, could be considered an interesting molecular therapeutic modality in human AML independent of its subtype.

publication date

  • October 27, 2017

Research

keywords

  • Enzyme Inhibitors
  • Gene Expression Regulation, Enzymologic
  • Gene Expression Regulation, Leukemic
  • Histone Demethylases
  • Jumonji Domain-Containing Histone Demethylases
  • Leukemia, Myeloid, Acute
  • Neoplasm Proteins
  • Nuclear Proteins

Identity

Scopus Document Identifier

  • 85036610842

Digital Object Identifier (DOI)

  • 10.1016/j.exphem.2017.10.002

PubMed ID

  • 29111428

Additional Document Info

volume

  • 58