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

Steven Goossens, Sofie Peirs, Wouter Van Loocke, Jueqiong Wang, Mina Takawy, Filip Matthijssens, Stefan E. Sonderegger, Katharina Haigh, Thao Nguyen, Niels Vandamme, Magdaline Costa, Catherine Carmichael, Filip Van Nieuwerburgh, Dieter Deforce, Oded Kleifeld, David J. Curtis, Geert Berx, Pieter Van Vlierberghe and Jody J. Haigh

Key points

  • ZEB2, a novel driver of immature T-cell acute lymphoblastic leukemia (T-ALL), interacts with the Lysine-specific demethylase KDM1A

  • KDM1A function is critical for leukemic survival of T-ALL cells with high ZEB2 levels

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.

  • Submitted June 7, 2016.
  • Accepted December 22, 2016.