Faculty, Staff and Student Publications

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

DOI

10.1016/j.ccell.2024.03.003

PMID

38593781

PMCID

PMC11008188

PubMedCentral® Posted Date

April 2024

PubMedCentral® Full Text Version

Author MSS

Published Open-Access

yes

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