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
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.
- Copyright © 2017 American Society of Hematology
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