1. Network-based systems pharmacology reveals heterogeneity in LCK and BCL2 signaling and therapeutic sensitivity of T-cell acute lymphoblastic leukemia.
- Author
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Gocho Y, Liu J, Hu J, Yang W, Dharia NV, Zhang J, Shi H, Du G, John A, Lin TN, Hunt J, Huang X, Ju B, Rowland L, Shi L, Maxwell D, Smart B, Crews KR, Yang W, Hagiwara K, Zhang Y, Roberts K, Wang H, Jabbour E, Stock W, Eisfelder B, Paietta E, Newman S, Roti G, Litzow M, Easton J, Zhang J, Peng J, Chi H, Pounds S, Relling MV, Inaba H, Zhu X, Kornblau S, Pui CH, Konopleva M, Teachey D, Mullighan CG, Stegmaier K, Evans WE, Yu J, and Yang JJ
- Subjects
- Cell Line, Tumor, Dasatinib pharmacology, Humans, Network Pharmacology, Proto-Oncogene Proteins c-bcl-2 genetics, T-Lymphocytes, Precursor T-Cell Lymphoblastic Leukemia-Lymphoma drug therapy
- Abstract
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 that 44.4% of childhood and 16.7% of adult T-ALL cases exquisitely respond to dasatinib. Applying network-based systems pharmacology analyses to examine signal circuitry, we identified preTCR-LCK activation as the driver of dasatinib sensitivity, and T-ALL-specific LCK dependency was confirmed in genome-wide CRISPR-Cas9 screens. Dasatinib-sensitive T-ALLs exhibited high BCL-XL and low BCL2 activity and venetoclax resistance. Discordant sensitivity of T-ALL to dasatinib and venetoclax is strongly correlated with T-cell differentiation, particularly with the dynamic shift in LCK vs. BCL2 activation. Finally, single-cell analysis identified leukemia heterogeneity in LCK and BCL2 signaling and T-cell maturation stage, consistent with dasatinib response. In conclusion, our results indicate that developmental arrest in T-ALL drives differential activation of preTCR-LCK and BCL2 signaling in this leukemia, providing unique opportunities for targeted therapy.
- Published
- 2021
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