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Network-based systems pharmacology identifies heterogeneity in LCK and BCL2 signaling and differential vulnerability of T-cell acute lymphoblastic leukemia to targeted therapy

T-cell acute lymphoblastic leukemia (T-ALL) is an aggressive hematological malignancy, and novel therapeutics are much needed. Profiling patient leukemia’ drug sensitivities ex vivo, we discovered striking inter-patient variability in T-ALL response to a panel of targeted agents. Applying network-based systems pharmacology analyses, by integrating ex vivo pharmacotyping, bulk and single-cell RNA-seq, genomics, phospho-proteomics, and genome-wide CRISPR screening data, to examine signal circuitry, we identified the pharmacogenomic basis of T-ALL drug response and revealed a therapeutic vulnerability that is directly related to the developmental stage of leukemia cells. In conclusion, our results indicate that heterogeneity in the differentiation of T-ALL drives activation of key signaling pathways in this leukemia, providing unique opportunities for targeted therapy.

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Dataset ID Description Technology Samples
EGAD00001006434 Illumina NovaSeq 6000 44
Publications Citations
Network-based systems pharmacology reveals heterogeneity in LCK and BCL2 signaling and therapeutic sensitivity of T-cell acute lymphoblastic leukemia.
Nat Cancer 2: 2021 284-299