Publications & Reports

Oncogenic ZEB2 activation drives sensitivity towards KDM1A inhibition in T-cell acute lymphoblastic leukemia.

Goossens S, Peirs S, Van Loocke W, Wang J, Takawy M, Matthijssens F, Sonderegger SE, Haigh K, Nguyen T, Vandamme N, Costa M, Carmichael C, Van Nieuwerburgh F, Deforce D, Kleifeld O, Curtis DJ, Berx G, Van Vlierberghe P, Haigh JJ

Abstract

Elevated expression of the Zinc finger E-box binding homeobox transcription factor-2 (ZEB2) is correlated with poor prognosis and patient outcome in a variety of human cancer subtypes. Using a conditional gain-of-function mouse model, we recently demonstrated that ZEB2 is an oncogenic driver of immature T-cell acute lymphoblastic leukemia (T-ALL), a heterogenic subgroup of human leukemia characterized by a high incidence of remission failure or hematological relapse after conventional chemotherapy. Here, we identified the Lysine-specific demethylase KDM1A as a novel interaction partner of ZEB2 and demonstrated that mouse and human T-ALLs with increased ZEB2 levels critically depend on KDM1A activity for survival. Therefore, targeting the ZEB2 protein complex through direct disruption of the ZEB2-KDM1A interaction or pharmacological inhibition of the KDM1A demethylase activity itself, could serve as a novel therapeutic strategy for this aggressive subtype of human leukemia, and possibly other ZEB2-driven malignancies.

Link to Pubmed

Publication

  • Journal: Blood
  • Published: 09/01/2017
  • Volume: Epub ahead of print

Author