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Ferrata Storti Foundation
Haematologica 2021 Volume 106(7):1816-1827
Acute Lymphoblastic Leukemia
WEE1 inhibition induces glutamine addiction in T-cell acute lymphoblastic leukemia
Juncheng Hu,1,2,* Tianci Wang,1,2,* Jin Xu,2 Sanyun Wu,1 Liyuan Wang,2
Hexiu Su,2 Jue Jiang,2 Ming Yue,3 Jingchao Wang,2 Donghai Wang,2 Peng Li,4 Fuling Zhou,1 Yu Liu,5 Guoliang Qing2 and Hudan Liu1,2
1Department of Hematology, Zhongnan Hospital, Wuhan University, Wuhan; 2Frontier Science Center for Immunology and Metabolism, Medical Research Institute, Wuhan University, Wuhan; 3Department of Pharmacy, The Central Hospital of Wuhan, Tongji
4
Medical College, Huazhong University of Science and Technology, Wuhan; South China
Institute for Stem Cell Biology and Regenerative Medicine, Guangzhou Institutes of Biomedicine and Health, Chinese Academy of Sciences, Guangzhou and 5Pediatric Translational Medicine Institute, Shanghai Children’s Medical Center, Shanghai Jiao Tong University School of Medicine, Shanghai, China
*JH and TW contributed equally as co-first authors.
ABSTRACT
Tcell acute lymphoblastic leukemias (T-ALL) are aggressive and het- erogeneous hematologic tumors resulting from the malignant transformation of T-cell progenitors. The major challenges in the treatment of T-ALL are dose-limiting toxicities of chemotherapeutics and drug resistance. Despite important progress in deciphering the genomic landscape of T-ALL, translation of these findings into effective targeted therapies remains largely unsuccessful. New targeted agents with signif- icant antileukemic efficacy and less toxicity are urgently needed. Here we report that the expression of WEE1, a nuclear tyrosine kinase involved in cell cycle G2-M checkpoint signaling, is significantly elevated in T-ALL. Mechanistically, oncogenic MYC directly binds to the WEE1 promoter and activates its transcription. T-ALL cells particularly rely on the elevated WEE1 for cell viability. Pharmacological inhibition of WEE1 elicits global metabolic reprogramming which results in a marked sup- pression of aerobic glycolysis in T-ALL cells, leading to an increased dependency on glutaminolysis for cell survival. As such, dual targeting of WEE1 and glutaminase (GLS1) induces synergistic lethality in multiple T- ALL cell lines and shows great efficacy in T-ALL patient-derived xenografts. These findings provide mechanistic insights into the regula- tion of WEE1 kinase in T-ALL and suggest an additional vulnerability during WEE1 inhibitor treatments. We also highlight a promising combi- nation strategy of dual inhibition of cell cycle kinase and metabolic enzymes for T-ALL therapeutics.
Introduction
T-cell acute lymphoblastic leukemias (T-ALL) are highly proliferative hematolog- ic tumors,1 which represent 10-15% of pediatric and 25% of adult acute lym- phoblastic leukemia cases.2 Introduction of intensified chemotherapy protocols in T-ALL treatment significantly improves the overall survival in pediatric patients.3 Despite this progress, chemotherapeutic treatments come with significant short- term and long-term side effects4 and the prognosis of patients with resistant or relapsed diseases remains dismal.5 Moreover, the remarkable success of pediatric treatment has not been achieved in adult patients as they do not always tolerate intensive pediatric regimens.6 Identification of activating mutations in NOTCH1 in over 50% of T-ALL cases has stimulated much interest in the development of anti- NOTCH1 therapies. However, the clinical development of γ-secretase inhibitors (GSI), which block a critical proteolytic step required for NOTCH1 activation, has been hampered by limited efficacies in human patients and significant gastrointestinal toxicity.7 Facing these clinical challenges, new tar-
Correspondence:
HUDAN LIU
hudanliu@whu.edu.cn
Received: July 2, 2019. Accepted: January 2, 2020. Pre-published: January 9, 2020.
https://doi.org/10.3324/haematol.2019.231126
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