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| Status |
Public on Jan 05, 2021 |
| Title |
Network-based systems pharmacology identifies heterogeneity in LCK and BCL2 signaling and differential vulnerability of T-cell acute lymphoblastic leukemia to targeted therapy |
| Organism |
Homo sapiens |
| Experiment type |
Expression profiling by high throughput sequencing
|
| Summary |
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.
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| |
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| Overall design |
10xGenomics scRNA-seq profiles of T-ALL PDX with or without Dasatinib treatment
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| |
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| Contributor(s) |
Yu J, Yang JJ, Liu J, Hu J |
| Citation missing |
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| |
| Submission date |
Sep 23, 2020 |
| Last update date |
Jan 06, 2021 |
| Contact name |
Jiyang Yu |
| E-mail(s) |
jiyang.yu@stjude.org
|
| Organization name |
stjude children's research hospital
|
| Department |
Dept. of computational biology
|
| Street address |
262 Danny Thomas Pl
|
| City |
Memphis |
| State/province |
TN |
| ZIP/Postal code |
38105-3678 |
| Country |
USA |
| |
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| Platforms (1) |
| GPL20301 |
Illumina HiSeq 4000 (Homo sapiens) |
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| Samples (4)
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| Relations |
| BioProject |
PRJNA665257 |
| SRA |
SRP285133 |
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