Oncogenic ZEB2 activation drives sensitivity toward 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, Jody J Haigh

Research output: Contribution to journalArticleResearchpeer-review

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.

Original languageEnglish
Pages (from-to)981-990
Number of pages10
JournalBlood
Volume129
Issue number8
DOIs
Publication statusPublished - 23 Feb 2017

Cite this

Goossens, S., Peirs, S., Loocke, W. V., Wang, J., Takawy, M., Matthijssens, F., ... Haigh, J. J. (2017). Oncogenic ZEB2 activation drives sensitivity toward KDM1A inhibition in T-cell acute lymphoblastic leukemia. Blood, 129(8), 981-990. https://doi.org/10.1182/blood-2016-06-721191
Goossens, Steven ; Peirs, Sofie ; Loocke, Wouter Van ; Wang, Jueqiong ; Takawy, Mina ; Matthijssens, Filip ; Sonderegger, Stefan E. ; Haigh, Katharina ; Nguyen, Thao ; Vandamme, Niels ; Costa, Magdaline ; Carmichael, Catherine ; Van Nieuwerburgh, Filip ; Deforce, Dieter ; Kleifeld, Oded ; Curtis, David J ; Berx, Geert ; Van Vlierberghe, Pieter ; Haigh, Jody J. / Oncogenic ZEB2 activation drives sensitivity toward KDM1A inhibition in T-cell acute lymphoblastic leukemia. In: Blood. 2017 ; Vol. 129, No. 8. pp. 981-990.
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title = "Oncogenic ZEB2 activation drives sensitivity toward KDM1A inhibition in T-cell acute lymphoblastic leukemia",
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 = "Steven Goossens and Sofie Peirs and Loocke, {Wouter Van} and Jueqiong Wang and Mina Takawy and Filip Matthijssens and Sonderegger, {Stefan E.} and Katharina Haigh and Thao Nguyen and Niels Vandamme and Magdaline Costa and Catherine Carmichael and {Van Nieuwerburgh}, Filip and Dieter Deforce and Oded Kleifeld and Curtis, {David J} and Geert Berx and {Van Vlierberghe}, Pieter and Haigh, {Jody J}",
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Goossens, S, Peirs, S, Loocke, WV, Wang, J, Takawy, M, Matthijssens, F, Sonderegger, SE, Haigh, K, Nguyen, T, Vandamme, N, Costa, M, Carmichael, C, Van Nieuwerburgh, F, Deforce, D, Kleifeld, O, Curtis, DJ, Berx, G, Van Vlierberghe, P & Haigh, JJ 2017, 'Oncogenic ZEB2 activation drives sensitivity toward KDM1A inhibition in T-cell acute lymphoblastic leukemia' Blood, vol. 129, no. 8, pp. 981-990. https://doi.org/10.1182/blood-2016-06-721191

Oncogenic ZEB2 activation drives sensitivity toward KDM1A inhibition in T-cell acute lymphoblastic leukemia. / Goossens, Steven; Peirs, Sofie; Loocke, Wouter Van; Wang, Jueqiong; Takawy, Mina; Matthijssens, Filip; Sonderegger, Stefan E.; Haigh, Katharina; Nguyen, Thao ; Vandamme, Niels; Costa, Magdaline; Carmichael, Catherine; Van Nieuwerburgh, Filip; Deforce, Dieter; Kleifeld, Oded; Curtis, David J; Berx, Geert; Van Vlierberghe, Pieter; Haigh, Jody J.

In: Blood, Vol. 129, No. 8, 23.02.2017, p. 981-990.

Research output: Contribution to journalArticleResearchpeer-review

TY - JOUR

T1 - Oncogenic ZEB2 activation drives sensitivity toward KDM1A inhibition in T-cell acute lymphoblastic leukemia

AU - Goossens, Steven

AU - Peirs, Sofie

AU - Loocke, Wouter Van

AU - Wang, Jueqiong

AU - Takawy, Mina

AU - Matthijssens, Filip

AU - Sonderegger, Stefan E.

AU - Haigh, Katharina

AU - Nguyen, Thao

AU - Vandamme, Niels

AU - Costa, Magdaline

AU - Carmichael, Catherine

AU - Van Nieuwerburgh, Filip

AU - Deforce, Dieter

AU - Kleifeld, Oded

AU - Curtis, David J

AU - Berx, Geert

AU - Van Vlierberghe, Pieter

AU - Haigh, Jody J

PY - 2017/2/23

Y1 - 2017/2/23

N2 - 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.

AB - 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.

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U2 - 10.1182/blood-2016-06-721191

DO - 10.1182/blood-2016-06-721191

M3 - Article

VL - 129

SP - 981

EP - 990

JO - Blood

JF - Blood

SN - 0006-4971

IS - 8

ER -

Goossens S, Peirs S, Loocke WV, Wang J, Takawy M, Matthijssens F et al. Oncogenic ZEB2 activation drives sensitivity toward KDM1A inhibition in T-cell acute lymphoblastic leukemia. Blood. 2017 Feb 23;129(8):981-990. https://doi.org/10.1182/blood-2016-06-721191