gsk2879552 and Precursor-T-Cell-Lymphoblastic-Leukemia-Lymphoma

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.

Topics: Animals; Benzoates; Cell Line, Tumor; Cyclopropanes; Gene Expression Regulation, Leukemic; Histone Demethylases; Homeodomain Proteins; Humans; Mice; Mice, Inbred NOD; Mice, SCID; Precursor T-Cell Lymphoblastic Leukemia-Lymphoma; Protein Interaction Maps; Repressor Proteins; Up-Regulation; Zinc Finger E-box Binding Homeobox 2