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Single-cell systems pharmacology identifies development-driven drug response and combination therapy in B cell acute lymphoblastic leukemia by Xin Huang; Yizhen Li; Jingliao Zhang; Lei Yan; Huanbin Zhao; Liang Ding; Sheetal Bhatara; Xu Yang; Satoshi Yoshimura; Wenjian Yang; Seth E. Karol; Hiroto Inaba; Charles Mullighan; Mark Litzow; Xiaofan Zhu; Yingchi Zhang; Wendy Stock; Nitin Jain; Elias Jabbour; Steven M. Kornblau; Marina Konopleva; Ching-Hon Pui; Elisabeth Paietta; William Evans; Jiyang Yu; Jun J. Yang is a Biochemistry, Genetics and Molecular Biology article available to read on EtoBox.

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## SUMMARY 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.

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Author

Xin Huang; Yizhen Li; Jingliao Zhang; Lei Yan; Huanbin Zhao; Liang Ding; Sheetal Bhatara; Xu Yang; Satoshi Yoshimura; Wenjian Yang; Seth E. Karol; Hiroto Inaba; Charles Mullighan; Mark Litzow; Xiaofan Zhu; Yingchi Zhang; Wendy Stock; Nitin Jain; Elias Jabbour; Steven M. Kornblau; Marina Konopleva; Ching-Hon Pui; Elisabeth Paietta; William Evans; Jiyang Yu; Jun J. Yang

Publisher

Elsevier BV

Published

2024

Language

EN

Field

Biochemistry, Genetics and Molecular Biology (Life Sciences)