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

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.
Competing Interests: Declaration of interests S.E.K. has consulted Servier, Inc. and Jazz Pharmaceuticals. C.M. receives research funding from AbbVie and Pfizer, honoraria from Amgen and Illumina, and royalty payments from Cyrus. C.M. is on an advisory board for Illumina. M.K. receives grants from AbbVie, Allogene, Astra Zeneca, Cellectis, Daiichi, Forty Seven, Genentech, Gilead, MEI Pharma, Precision Bio, Rafael Pharmaceutical, Sanofi, and Stemline-Menarini; personal fees from AbbVie, AstraZeneca, Auxenion, Genentech, Gilead, F. Hoffman-La Roche, Janssen, MEI Pharma, Sellas, and Stemline-Menarini. In addition, M.K. has a patent US 7,795,305 B2 CDDO-compounds and combination therapies with royalties paid to Reata Pharm., a patent Combination Therapy with a mutant IDH1 Inhibitor and a BCL-2 licensed to Eli Lilly, and a patent 62/993,166 combination of a mcl-1 inhibitor and midostaurin, uses and pharmaceutical compositions thereof pending to Novartis. J.J.Y. receives funding from Takeda Pharmaceutical Company and AstraZeneca plc for research unrelated to this work.
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