WEE1 inhibition induces glutamine addiction in T-cell acute lymphoblastic leukemia.
WEE1 inhibition induces glutamine addiction in T-cell acute lymphoblastic leukemia.
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WEE1 抑制诱导 T 细胞急性淋巴细胞白血病谷氨酰胺成瘾
DOI：
10.3324/haematol.2019.231126
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发表时间：
2021-07-01
期刊：
影响因子：
10.1
通讯作者：
Liu H
中科院分区：
文献类型：
--
作者：
Hu J;Wang T;Xu J;Wu S;Wang L;Su H;Jiang J;Yue M;Wang J;Wang D;Li P;Zhou F;Liu Y;Qing G;Liu H
T细胞急性淋巴细胞性白血病(T-ALL)是一种侵袭性、异质性的血液肿瘤，由T细胞前体细胞恶性转化所致。治疗T-ALL的主要挑战是化疗药物的剂量限制毒性和耐药性。尽管在破译T-ALL的基因组图谱方面取得了重要进展，但将这些发现转化为有效的靶向治疗仍然很大程度上不成功。迫切需要抗白血病疗效显著、毒性小的新靶向药物。在此，我们报道了参与细胞周期G2-M检查点信号转导的核酪氨酸激酶WEE1在T-ALL中的表达显著升高。在机制上，致癌的MYC直接与WEE1启动子结合并激活其转录。T-ALL细胞尤其依赖升高的WEE1来维持细胞活力。WEE1的药物抑制引起全球代谢重编程，导致T-ALL细胞有氧糖酵解的显著抑制，导致细胞生存对谷氨酰胺分解的依赖增加。因此，WEE1和谷氨酰胺酶(GLS1)的双靶向在多个Tall细胞系中诱导协同致死，并在T-ALL患者来源的异种移植中显示出巨大的疗效。这些发现提供了对T-ALL中WEE1激酶调节的机械性见解，并提示在WEE1抑制剂治疗过程中存在额外的脆弱性。我们还强调了T-ALL疗法中双重抑制细胞周期激酶和代谢酶的有前景的组合策略。
Tcell acute lymphoblastic leukemias (T-ALL) are aggressive and heterogeneous 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 significant 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 suppression 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 TALL cell lines and shows great efficacy in T-ALL patient-derived xenografts. These findings provide mechanistic insights into the regulation of WEE1 kinase in T-ALL and suggest an additional vulnerability during WEE1 inhibitor treatments. We also highlight a promising combination strategy of dual inhibition of cell cycle kinase and metabolic enzymes for T-ALL therapeutics.