T-cell acute lymphoblastic leukemia (T-ALL) is an aggressive hematological malignancy and new 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-ALL exhibited high BCL-XL activity, 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 versus 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.

Network-based systems pharmacology reveals heterogeneity in LCK and BCL2 signaling and therapeutic sensitivity of T-cell acute lymphoblastic leukemia / Gocho, Y.; Liu, J.; Hu, J.; Yang, W.; Dharia, N. V.; Zhang, J.; Shi, H.; Du, G.; John, A.; Lin, T. -N.; Hunt, J.; Huang, X.; Ju, B.; Rowland, L.; Shi, L.; Maxwell, D.; Smart, B.; Crews, K. R.; 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, M. V.; Inaba, H.; Zhu, X.; Kornblau, S.; Pui, C. -H.; Konopleva, M.; Teachey, D.; Mullighan, C. G.; Stegmaier, K.; Evans, W. E.; Yu, J.; Yang, J. J.. - In: NATURE CANCER. - ISSN 2662-1347. - (2021). [10.1038/s43018-020-00167-4]

Network-based systems pharmacology reveals heterogeneity in LCK and BCL2 signaling and therapeutic sensitivity of T-cell acute lymphoblastic leukemia

Roti G.;
2021

Abstract

T-cell acute lymphoblastic leukemia (T-ALL) is an aggressive hematological malignancy and new 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-ALL exhibited high BCL-XL activity, 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 versus 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.
Network-based systems pharmacology reveals heterogeneity in LCK and BCL2 signaling and therapeutic sensitivity of T-cell acute lymphoblastic leukemia / Gocho, Y.; Liu, J.; Hu, J.; Yang, W.; Dharia, N. V.; Zhang, J.; Shi, H.; Du, G.; John, A.; Lin, T. -N.; Hunt, J.; Huang, X.; Ju, B.; Rowland, L.; Shi, L.; Maxwell, D.; Smart, B.; Crews, K. R.; 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, M. V.; Inaba, H.; Zhu, X.; Kornblau, S.; Pui, C. -H.; Konopleva, M.; Teachey, D.; Mullighan, C. G.; Stegmaier, K.; Evans, W. E.; Yu, J.; Yang, J. J.. - In: NATURE CANCER. - ISSN 2662-1347. - (2021). [10.1038/s43018-020-00167-4]
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Utilizza questo identificativo per citare o creare un link a questo documento: http://hdl.handle.net/11381/2888082
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