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

(2017) BLOOD. 129(8). p.981-990
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HPC-UGent: the central High Performance Computing infrastructure of Ghent University
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.
Keywords
EPITHELIAL-MESENCHYMAL TRANSITION, HISTONE DEMETHYLASE LSD1, ACUTE, MYELOID-LEUKEMIA, HEMATOPOIETIC STEM-CELLS, TRANSCRIPTIONAL REPRESSION, MALIGNANT-TRANSFORMATION, TERMINAL DIFFERENTIATION, BREAST-CANCER, FEEDBACK LOOP, E-CADHERIN

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Citation

Please use this url to cite or link to this publication:

Chicago
Goossens, Steven, Sofie Peirs, Wouter Van Loocke, Jueqiong Wang, Mina Takawy, Filip Matthijssens, Stefan E Sonderegger, et al. 2017. “Oncogenic ZEB2 Activation Drives Sensitivity Toward KDM1A Inhibition in T-cell Acute Lymphoblastic Leukemia.” Blood 129 (8): 981–990.
APA
Goossens, S., Peirs, S., Van Loocke, W., Wang, J., Takawy, M., Matthijssens, F., Sonderegger, S. E., et al. (2017). Oncogenic ZEB2 activation drives sensitivity toward KDM1A inhibition in T-cell acute lymphoblastic leukemia. BLOOD, 129(8), 981–990.
Vancouver
1.
Goossens S, Peirs S, Van Loocke W, Wang J, Takawy M, Matthijssens F, et al. Oncogenic ZEB2 activation drives sensitivity toward KDM1A inhibition in T-cell acute lymphoblastic leukemia. BLOOD. 2017;129(8):981–90.
MLA
Goossens, Steven, Sofie Peirs, Wouter Van Loocke, et al. “Oncogenic ZEB2 Activation Drives Sensitivity Toward KDM1A Inhibition in T-cell Acute Lymphoblastic Leukemia.” BLOOD 129.8 (2017): 981–990. Print.
@article{8528674,
  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.},
  author       = {Goossens, Steven and Peirs, Sofie and Van Loocke, Wouter and Wang, Jueqiong and Takawy, Mina and Matthijssens, Filip and Sonderegger, Stefan E and Haigh, Katharina and Nguyen, Thao and Vandamme, Niels and Costa, Magdaline and Carmichael, Catherine and Van Nieuwerburgh, Filip and Deforce, Dieter and Kleifeld, Oded and Curtis, David J and Berx, Geert and Van Vlierberghe, Pieter and Haigh, Jody J},
  issn         = {0006-4971},
  journal      = {BLOOD},
  language     = {eng},
  number       = {8},
  pages        = {981--990},
  title        = {Oncogenic ZEB2 activation drives sensitivity toward KDM1A inhibition in T-cell acute lymphoblastic leukemia},
  url          = {http://dx.doi.org/10.1182/blood-2016-06-721191},
  volume       = {129},
  year         = {2017},
}

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