Leukemia can arise at various stages of the hematopoietic differentiation hierarchy, but the impact of developmental arrest on drug sensitivity is unclear. Applying network-based analyses to single-cell transcriptomes of human B cells, we define genome-wide signaling circuitry for each B cell differentiation stage. Using this reference, we comprehensively map the developmental states of B cell acute lymphoblastic leukemia (B-ALL), revealing its strong correlation with sensitivity to asparaginase, a commonly used chemotherapeutic agent. Single-cell multi-omics analyses of primary B-ALL blasts reveal marked intra-leukemia heterogeneity in asparaginase response: resistance is linked to pre-pro-B-like cells, with sensitivity associated with the pro-B-like population. By targeting BCL2, a driver within the pre-pro-B-like cell signaling network, we find that venetoclax significantly potentiates asparaginase efficacy in vitro and in vivo. These findings demonstrate a single-cell systems pharmacology framework to predict effective combination therapies based on intra-leukemia heterogeneity in developmental state, with potentially broad applications beyond B-ALL.

白血病可发生在造血分化层次的各个阶段，但发育停滞对药物敏感性的影响尚不清楚。通过将基于网络的分析应用于人类 B 细胞的单细胞转录组，我们定义了每个 B 细胞分化阶段的全基因组信号通路。利用这一参考资料，我们全面绘制了 B 细胞急性淋巴细胞白血病 (B-ALL) 的发育状态，揭示了其与对常用化疗药物天冬酰胺酶的敏感性密切相关。原代 B-ALL 母细胞的单细胞多组学分析揭示了天冬酰胺酶反应中明显的白血病内异质性：耐药性与前 B 样细胞相关，敏感性与 B 样细胞群体相关。通过靶向 BCL2（前原 B 样细胞信号传导网络中的驱动程序），我们发现 Venetoclax 显着增强了天冬酰胺酶的体外和体内功效。这些发现证明了一个单细胞系统药理学框架，可以根据发育状态的白血病内异质性预测有效的联合疗法，具有除 B-ALL 之外的潜在广泛应用。