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

Yoshihiro Gocho, Jingjing Liu, Jianzhong Hu, Wentao Yang, Neekesh V. Dharia, Jingliao Zhang, Hao Shi, Guoqing Du, August John, Ting Nien Lin, Jeremy Hunt, Xin Huang, Bensheng Ju, Lauren Rowland, Lei Shi, Dylan Maxwell, Brandon Smart, Kristine R. Crews, Wenjian Yang, Kohei HagiwaraYingchi Zhang, Kathryn Roberts, Hong Wang, Elias Jabbour, Wendy Stock, Bartholomew Eisfelder, Elisabeth Paietta, Scott Newman, Giovanni Roti, Mark Litzow, John Easton, Jinghui Zhang, Junmin Peng, Hongbo Chi, Stanley Pounds, Mary V. Relling, Hiroto Inaba, Xiaofan Zhu, Steven Kornblau, Ching Hon Pui, Marina Konopleva, David Teachey, Charles G. Mullighan, Kimberly Stegmaier, William E. Evans, Jiyang Yu, Jun J. Yang

Research output: Contribution to journalArticlepeer-review

1 Scopus citations

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.

Original languageEnglish (US)
Pages (from-to)284-299
Number of pages16
JournalNature Cancer
Volume2
Issue number3
DOIs
StatePublished - Mar 2021

ASJC Scopus subject areas

  • Oncology
  • Cancer Research

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