The deregulation of BCL2 family proteins plays a crucial role in leukemia development. Therefore, pharmacological inhibition of this family of proteins is becoming a prevalent treatment method. However, due to the emergence of primary and acquired resistance, efficacy is compromised in clinical or preclinical settings. We developed a drug sensitivity prediction model utilizing a deep tabular learning algorithm for the assessment of venetoclax sensitivity in T-cell acute lymphoblastic leukemia (T-ALL) patient samples. Through analysis of predicted venetoclax-sensitive and resistant samples, PLK1 was identified as a cooperating partner for the BCL2-mediated antiapoptotic program. This finding was substantiated by additional data obtained through phosphoproteomics and high-throughput kinase screening. Concurrent treatment using venetoclax with PLK1-specific inhibitors and PLK1 knockdown demonstrated a greater therapeutic effect on T-ALL cell lines, patient-derived xenografts, and engrafted mice compared with using each treatment separately. Mechanistically, the attenuation of PLK1 enhanced BCL2 inhibitor sensitivity through upregulation of BCL2L13 and PMAIP1 expression. Collectively, these findings underscore the dependency of T-ALL on PLK1 and postulate a plausible regulatory mechanism.
BCL2家族蛋白的失调在白血病发展中起着至关重要的作用。因此，对该蛋白家族进行药理学抑制已成为一种主流的治疗方法。然而，由于原发性和获得性耐药的出现，该方法在临床或临床前环境中的疗效受到限制。我们利用深度表格学习算法开发了一种药物敏感性预测模型，用于评估T细胞急性淋巴细胞白血病（T-ALL）患者样本对venetoclax的敏感性。通过对预测为venetoclax敏感与耐药样本的分析，发现PLK1是BCL2介导的抗凋亡程序的协同作用因子。这一发现通过磷酸化蛋白质组学和高通量激酶筛选的进一步数据得到了证实。相较于单独使用任一治疗方法，venetoclax与PLK1特异性抑制剂联合治疗以及PLK1敲除在T-ALL细胞系、患者来源异种移植模型及移植小鼠中均表现出更强的治疗效果。机制上，PLK1的减弱通过上调BCL2L13和PMAIP1的表达增强了BCL2抑制剂的敏感性。总之，这些发现强调了T-ALL对PLK1的依赖性，并提出了一种可能的调控机制。
PLK1 as a cooperating partner for BCL2-mediated antiapoptotic program in leukemia
肿瘤(癌症)患者之家