Laboratory of Onco-Hematology, Assistance Publique-Hôpitaux de Paris (AP-HP), Hôpital Necker Enfants-Malades, Paris, France.
INSERM Unité Mixte de Recherche en Santé (UMRS) 1131, Institut Universitaire d'Hématologie, Hôpital Saint-Louis, Paris, France.
Blood Adv. 2021 Feb 9;5(3):700-710. doi: 10.1182/bloodadvances.2020002700.
T-cell acute lymphoblastic leukemia (T-ALL) represents the malignant expansion of immature T cells blocked in their differentiation. T-ALL is still associated with a poor prognosis, mainly related to occurrence of relapse or refractory disease. A critical medical need therefore exists for new therapies to improve the disease prognosis. Adenylate kinase 2 (AK2) is a mitochondrial kinase involved in adenine nucleotide homeostasis recently reported as essential in normal T-cell development, as defective AK2 signaling pathway results in a severe combined immunodeficiency with a complete absence of T-cell differentiation. In this study, we show that AK2 is constitutively expressed in T-ALL to varying levels, irrespective of the stage of maturation arrest or the underlying oncogenetic features. T-ALL cell lines and patient T-ALL-derived xenografts present addiction to AK2, whereas B-cell precursor ALL cells do not. Indeed, AK2 knockdown leads to early and massive apoptosis of T-ALL cells that could not be rescued by the cytosolic isoform AK1. Mechanistically, AK2 depletion results in mitochondrial dysfunction marked by early mitochondrial depolarization and reactive oxygen species production, together with the depletion of antiapoptotic molecules (BCL-2 and BCL-XL). Finally, T-ALL exposure to a BCL-2 inhibitor (ABT-199 [venetoclax]) significantly enhances the cytotoxic effects of AK2 depletion. We also show that AK2 depletion disrupts the oxidative phosphorylation pathway. Combined with pharmaceutical inhibition of glycolysis, AK2 silencing prevents T-ALL metabolic adaptation, resulting in dramatic apoptosis. Altogether, we pinpoint AK2 as a genuine and promising therapeutic target in T-ALL.
T 细胞急性淋巴细胞白血病（T-ALL）代表幼稚 T 细胞恶性增殖，这些细胞在分化过程中受阻。T-ALL 仍然与预后不良相关，主要与复发或难治性疾病的发生有关。因此，迫切需要新的治疗方法来改善疾病预后。腺苷酸激酶 2（AK2）是一种参与腺嘌呤核苷酸稳态的线粒体激酶，最近有报道称其在正常 T 细胞发育中是必不可少的，因为 AK2 信号通路缺陷会导致严重的联合免疫缺陷，T 细胞分化完全缺失。在这项研究中，我们表明 AK2 在 T-ALL 中无论成熟阻滞的阶段或潜在的致癌遗传特征如何，都以不同水平持续表达。T-ALL 细胞系和患者 T-ALL 衍生的异种移植瘤对 AK2 有依赖性，而 B 细胞前体 ALL 细胞则没有。事实上，AK2 敲低会导致 T-ALL 细胞早期和大量凋亡，而这种凋亡不能被细胞质同工酶 AK1 挽救。从机制上讲，AK2 耗竭会导致线粒体功能障碍，表现为早期线粒体去极化和活性氧产生，以及抗凋亡分子（BCL-2 和 BCL-XL）的耗竭。最后，T-ALL 暴露于 BCL-2 抑制剂（ABT-199[venetoclax]）可显著增强 AK2 耗竭的细胞毒性作用。我们还表明，AK2 耗竭会破坏氧化磷酸化途径。与抑制糖酵解的药物联合使用，AK2 沉默可阻止 T-ALL 代谢适应，导致明显的细胞凋亡。总之，我们将 AK2 确定为 T-ALL 真正有前途的治疗靶点。
