应美丹团队通过肿瘤细胞代谢研究为儿童急髓白血病寻求治疗新靶点
专业点燃希望约 5 分钟撰文 | 邵雪晶 责编 | 周叶斌
近日，浙江大学药学院/附属儿童医院 应美丹教授 研究团队在 Blood 发表题为 Palmitoyltransferase ZDHHC21 regulates oxidative phosphorylation to induce differentiation block and stemness in AML 的文章，首次揭示了棕榈酰转移酶ZDHHC21是调控AML细胞OXPHOS异常激活的关键因子，阐明了ZDHHC21通过激活OXPHOS诱导AML细胞发生髓系分化障碍，并促进LSC细胞干性潜能的全新生物学作用，为儿童AML尤其是复发/难治患儿提供了治疗新靶点及干预新策略。
为了寻找AML细胞OXPHOS异常激活的关键机制，研究人员首先筛选了包含267个化合物的翻译后修饰酶抑制剂库，发现2个棕榈酰转移酶（ZDHHC）抑制剂均可选择性抑制AML细胞的OXPHOS活性。随后，研究人员引入了针对23个ZDHHCs蛋白的siRNA，进一步筛选并确认仅干扰ZDHHC21可选择性地抑制AML细胞的OXPHOS水平，且对造血干细胞基本没有影响。这些结果首次揭示了ZDHHC21是调控AML细胞OXPHOS异常激活的关键因子。
最后，靶向干预ZDHHC21可在整体动物水平有效抑制AML细胞的生长，并显著延长细胞系和患者来源细胞移植的白血病小鼠的生存时间。更为重要的是，抑制ZDHHC21可通过干扰OXPHOS活性有效清除PDX模型中复发/难治AML患者来源的白血病细胞，并显著提高其对一线化疗药物的敏感性，为复发/难治AML患者的临床治疗提供全新策略。
综上所述，该研究不仅揭示了棕榈酰转移酶ZDHHC21调控AML特别是LSC细胞线粒体氧化磷酸化的全新生物学功能，并提出抑制ZDHHC21作为儿童AML尤其是复发/难治患儿的潜在治疗策略，为儿童白血病的临床治疗提供全新药物靶点和思路。
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*本文由深圳市拾玉儿童公益基金会“儿童肿瘤前沿”团队编译或约稿，文中图表均源引自文献原文。本文著作权归文章作者所有，欢迎个人转发分享，未经允许禁止转载，作者拥有所有法定权利，违者必究。如需转载，请留言或联系[email protected]。本文旨在分享儿童肿瘤科研前沿成果，不是治疗方案推荐。如需获得疾病治疗方案指导，请前往正规医院就诊。
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原文摘要（Abstract）
Acute myeloid leukemia (AML) is an aggressive hematological malignancy. Nearly 50% of patients who receive the most intensive treatment inevitably suffer disease relapse, likely resulting from the persistence of drug‑resistant leukemia stem cells (LSCs). AML cells especially LSCs are highly dependent on mitochondrial oxidative phosphorylation (OXPHOS) for survival, but the mechanism involved in OXPHOS hyperactivity is unclear and a noncytotoxic strategy to inhibit OXPHOS is lacking. Here, we demonstrate for the first time that ZDHHC21 palmitoyltransferase serves as a key regulator of OXPHOS hyperactivity in AML cells. The depletion/inhibition of ZDHHC21 effectively induced myeloid differentiation and weakened stemness potential by inhibiting OXPHOS in AML cells. Interestingly, FLT3-ITD mutated AML cells expressed significantly higher levels of ZDHHC21 and exhibited better sensitivity to ZDHHC21 inhibition. Mechanistically, ZDHHC21 specifically catalyzed the palmitoylation of mitochondrial kinase AK2 and further activated OXPHOS in leukemic blasts. Inhibition of ZDHHC21 arrested the in vivo growth of AML cells and extended the survival of mice inoculated with AML cell lines and PDX-AML blasts. Moreover, targeting ZDHHC21 to suppress OXPHOS markedly eradicated AML blasts and enhanced chemotherapy efficacy in relapsed/refractory leukemia. Together, these findings not only uncover a new biological function of palmitoyltransferase ZDHHC21 in regulating AML oxidative phosphorylation, but also indicate that ZDHHC21 inhibition is a promising therapeutic regimen for patients with AML, especially relapsed/refractory leukemia.
DOI: 10.1182/blood.2022019056