Contrasting Roles of Histone 3 Lysine 27 Demethylases in Acute Lymphoblastic Leukaemia

Nature. 2014 Oct 23;514(7523):513-7. doi: 10.1038/nature13605. Epub 2014 Aug 17.

Abstract

T-cell acute lymphoblastic leukaemia (T-ALL) is a haematological malignancy with a dismal overall prognosis, including a relapse rate of up to 25%, mainly because of the lack of non-cytotoxic targeted therapy options. Drugs that target the function of key epigenetic factors have been approved in the context of haematopoietic disorders, and mutations that affect chromatin modulators in a variety of leukaemias have recently been identified; however, 'epigenetic' drugs are not currently used for T-ALL treatment. Recently, we described that the polycomb repressive complex 2 (PRC2) has a tumour-suppressor role in T-ALL. Here we delineated the role of the histone 3 lysine 27 (H3K27) demethylases JMJD3 and UTX in T-ALL. We show that JMJD3 is essential for the initiation and maintenance of T-ALL, as it controls important oncogenic gene targets by modulating H3K27 methylation. By contrast, we found that UTX functions as a tumour suppressor and is frequently genetically inactivated in T-ALL. Moreover, we demonstrated that the small molecule inhibitor GSKJ4 (ref. 5) affects T-ALL growth, by targeting JMJD3 activity. These findings show that two proteins with a similar enzymatic function can have opposing roles in the context of the same disease, paving the way for treating haematopoietic malignancies with a new category of epigenetic inhibitors.

Publication types

  • Research Support, N.I.H., Extramural
  • Research Support, Non-U.S. Gov't

MeSH terms

  • Animals
  • Benzazepines / pharmacology
  • Epigenesis, Genetic / drug effects
  • Histone Demethylases / genetics
  • Histone Demethylases / metabolism*
  • Histones / chemistry
  • Histones / metabolism
  • Jumonji Domain-Containing Histone Demethylases / antagonists & inhibitors
  • Jumonji Domain-Containing Histone Demethylases / metabolism*
  • Lysine / metabolism
  • Methylation / drug effects
  • Mice
  • Precursor Cell Lymphoblastic Leukemia-Lymphoma / drug therapy
  • Precursor Cell Lymphoblastic Leukemia-Lymphoma / enzymology*
  • Precursor Cell Lymphoblastic Leukemia-Lymphoma / genetics
  • Precursor Cell Lymphoblastic Leukemia-Lymphoma / pathology
  • Pyrimidines / pharmacology
  • Tumor Suppressor Proteins / genetics
  • Tumor Suppressor Proteins / metabolism

Substances

  • Benzazepines
  • GSK-J4
  • Histones
  • Pyrimidines
  • Tumor Suppressor Proteins
  • Histone Demethylases
  • Jumonji Domain-Containing Histone Demethylases
  • Utx protein, mouse
  • Kdm6b protein, mouse
  • Lysine

Associated data

  • GEO/GSE56696