Oncotarget

Research Papers:

Inhibition of the MAP2K7-JNK pathway with 5Z-7-oxozeaenol induces apoptosis in T-cell acute lymphoblastic leukemia

Taylor J. Chen, Wa Du, Jacob J. Junco, Cory Seth Bridges, Ye Shen, Monica Puppi, Karen R. Rabin and H. Daniel Lacorazza _

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Oncotarget. 2021; 12:1787-1801. https://doi.org/10.18632/oncotarget.28040

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Abstract

Taylor J. Chen1, Wa Du1, Jacob J. Junco2, Cory Seth Bridges1, Ye Shen1, Monica Puppi1, Karen R. Rabin2 and H. Daniel Lacorazza1

1 Department of Pathology & Immunology, Baylor College of Medicine, Houston, TX, USA

2 Texas Children’s Cancer Center, Department of Pediatrics, Baylor College of Medicine, Houston, TX, USA

Correspondence to:

H. Daniel Lacorazza, email: [email protected]

Keywords: T-ALL; MAP2K7; 5z-7-oxozeaenol

Received: June 30, 2021     Accepted: July 28, 2021     Published: August 31, 2021

Copyright: © 2021 Chen et al. This is an open access article distributed under the terms of the Creative Commons Attribution License (CC BY 3.0), which permits unrestricted use, distribution, and reproduction in any medium, provided the original author and source are credited.

ABSTRACT

T-cell acute lymphoblastic leukemia (T-ALL) is an aggressive pediatric leukemia with a worse prognosis than most frequent B-cell ALL due to a high incidence of treatment failures and relapse. Our previous work showed that loss of the pioneer factor KLF4 in a NOTCH1-induced T-ALL mouse model accelerated the development of leukemia through expansion of leukemia-initiating cells and activation of the MAP2K7 pathway. Similarly, epigenetic silencing of the KLF4 gene in children with T-ALL was associated with MAP2K7 activation. Here, we showed the small molecule 5Z-7-oxozeaenol (5Z7O) induces dose-dependent cytotoxicity in a panel of T-ALL cell lines mainly through inhibition of the MAP2K7-JNK pathway, which further validates MAP2K7 as a therapeutic target. Mechanistically, 5Z7O-mediated apoptosis was caused by the downregulation of regulators of the G2/M checkpoint and the inhibition of survival pathways. The anti-leukemic capacity of 5Z7O was evaluated using leukemic cells from two mouse models of T-ALL and patient-derived xenograft cells generated using lymphoblasts from pediatric T-ALL patients. Finally, a combination of 5Z7O with dexamethasone, a drug used in frontline therapy, showed synergistic induction of cytotoxicity. In sum, we report here that MAP2K7 inhibition thwarts survival mechanisms in T-ALL cells and warrants future pre-clinical studies for high-risk and relapsed patients.


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