Single-cell systems pharmacology identifies development-driven drug response and combination therapy in B cell acute lymphoblastic leukemia

• Published in: Cancer cell Vol. 42; no. 4; p. 552
• Main Authors: Huang, Xin, Li, Yizhen, Zhang, Jingliao, Yan, Lei, Zhao, Huanbin, Ding, Liang, Bhatara, Sheetal, Yang, Xu, Yoshimura, Satoshi, Yang, Wenjian, Karol, Seth E, Inaba, Hiroto, Mullighan, Charles, Litzow, Mark, Zhu, Xiaofan, Zhang, Yingchi, Stock, Wendy, Jain, Nitin, Jabbour, Elias, Kornblau, Steven M, Konopleva, Marina, Pui, Ching-Hon, Paietta, Elisabeth, Evans, William, Yu, Jiyang, Yang, Jun J
• Format: Journal Article
• Language: English
• Published: United States 08-04-2024
• Subjects: Asparaginase - pharmacology; Humans; Leukemia - drug therapy; Network Pharmacology; Precursor B-Cell Lymphoblastic Leukemia-Lymphoma - drug therapy; Precursor B-Cell Lymphoblastic Leukemia-Lymphoma - genetics; Signal Transduction; NetBID2; single-cell multiome; acute lymphoblastic leukemia; L-asparaginase; developmental origins; B cell development; hidden driver; venetoclax; single-cell systems pharmacology
• ISSN: 1878-3686
• DOI: 10.1016/j.ccell.2024.03.003

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.