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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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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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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.
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.
Chicago author-date
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.
Chicago author-date (all authors)
Goossens, Steven, 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. 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.
IEEE
[1]
S. Goossens et al., “Oncogenic ZEB2 activation drives sensitivity toward KDM1A inhibition in T-cell acute lymphoblastic leukemia,” BLOOD, vol. 129, no. 8, pp. 981–990, 2017.
@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},
  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},
  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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