Purpose: Systems biology approaches can identify critical targets in complex cancer signaling networks to inform new therapy combinations that may overcome conventional treatment resistance. Experimental Design: We performed integrated analysis of 1,046 childhood B-ALL cases and developed a data-driven network controllability-based approach to identify synergistic key regulator targets in Philadelphia chromosome–like B-acute lymphoblastic leukemia (Ph-like B-ALL), a common high-risk leukemia subtype associated with hyperactive signal transduction and chemoresistance. Results: We identified 14 dysregulated network nodes in Ph-like ALL involved in aberrant JAK/STAT, Ras/MAPK, and apoptosis pathways and other critical processes. Genetic cotargeting of the synergistic key regulator pair STAT5B and BCL2- associated athanogene 1 ( BAG1 ) significantly reduced leukemia cell viability in vitro . Pharmacologic inhibition with dual small molecule inhibitor therapy targeting this pair of key nodes further demonstrated enhanced antileukemia efficacy of combining the BCL-2 inhibitor venetoclax with the tyrosine kinase inhibitors ruxolitinib or dasatinib in vitro in human Ph-like ALL cell lines and in vivo in multiple childhood Ph-like ALL patient-derived xenograft models. Consistent with network controllability theory, co-inhibitor treatment also shifted the transcriptomic state of Ph-like ALL cells to become less like kinase-activated BCR-ABL1 –rearranged (Ph+) B-ALL and more similar to prognostically favorable childhood B-ALL subtypes. Conclusions: Our study represents a powerful conceptual framework for combinatorial drug discovery based on systematic interrogation of synergistic vulnerability pathways with pharmacologic inhibitor validation in preclinical human leukemia models. This article is featured in Highlights of This Issue, [p. 4945][1] [1]: /lookup/volpage/27/4945?iss=18

中文翻译：

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网络分析揭示了费城染色体样急性淋巴细胞白血病合理联合治疗的协同遗传依赖性

目的：系统生物学方法可以识别复杂癌症信号网络中的关键目标，为可能克服常规治疗耐药性的新治疗组合提供信息。实验设一种常见的高危白血病亚型，与过度活跃的信号转导和化学抗性有关。结果：我们在 Ph 样 ALL 中发现了 14 个失调的网络节点，这些节点涉及异常的 JAK/STAT、Ras/MAPK 和细胞凋亡途径和其他关键过程。协同关键调节因子对 STAT5B 和 BCL2 相关的 athanogene 1 (BAG1) 的遗传共靶向显着降低了体外白血病细胞的活力。针对这对关键节点的双重小分子抑制剂疗法的药理学抑制进一步证明了在体外人类 Ph 样 ALL 细胞系和体内多个儿童 Ph 样 ALL 患者来源的异种移植模型。与网络可控性理论一致，共抑制剂治疗还改变了 Ph 样 ALL 细胞的转录组状态，使其不像激酶激活的 BCR-ABL1 重排 (Ph+) B-ALL，更类似于预后良好的儿童 B-ALL 亚型. 结论：我们的研究代表了一个强大的组合药物发现概念框架，该框架基于在临床前人类白血病模型中对协同脆弱性途径和药理学抑制剂验证的系统询问。这篇文章被收录在本期的亮点中，[p. 4945][1][1]：/lookup/volpage/27/4945?iss=18