Single-Cell Systems Pharmacology Identifies Development-Driven Drug Response and Combination Therapy in B Cell Acute Lymphoblastic Leukemia

Authors

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

Publication Date

4-8-2024

Journal

Cancer Cell

Abstract

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.

Keywords

Humans, Asparaginase, Network Pharmacology, Precursor B-Cell Lymphoblastic Leukemia-Lymphoma, Signal Transduction, Leukemia

Comments

Supplementary Materials

PMID: 38593781