BCL2家族蛋白的解禁对白血病发展起着关键作用。因此，药物抑制该家族蛋白正在成为一种普遍的治疗方法。然而，由于初发性和后期获得性抗药性的出现，在临床或临床前环境中，疗效受到了损害。我们利用深度表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）患者样本的文替克瑞敏感性。通过对预测的文替克瑞敏感和耐药样本的分析，我们确定了PLK1作为BCL2介导的抗凋亡程序的合作伙伴。通过磷酸蛋白组学和高通量激酶筛选获得了额外的数据来证实这一发现。与单独使用每种治疗方法相比，同时使用具有PLK1特异性抑制剂和PLK1沉默的文替克瑞治疗对T-ALL细胞系、患者来源的异种移植体和移植小鼠展示出更大的治疗效果。在机制上，PLK1的抑制通过上调BCL2L13和PMAIP1的表达增强了BCL2抑制剂的敏感性。总的来说，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。© 2023. Springer Nature Limited.

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.© 2023. Springer Nature Limited.