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| Status |
Public on Mar 21, 2024 |
| Title |
Single-cell network pharmacology predicts total therapies targeting multiple developmental clones in B-cell acute lymphoblastic leukemia |
| Organism |
Homo sapiens |
| Experiment type |
Expression profiling by high throughput sequencing
Genome binding/occupancy profiling by high throughput sequencing
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| Summary |
Taking the advantage of the human bone marrow (BM) scRNA-seq in Human cell atlas census of immune cells study, we resolved B lineage into comprehensive human B-cell development stages and identified their landscape in B-ALL. L-asparaginase is the cornerstone of combination protocols in acute lymphoblastic leukemia (ALL). After profiled B cell acute lymphoblastic leukemia (B-ALL) patient drug sensitivities ex vivo and applied network-based systems pharmacology analyses to examine signal circuitry, we revealed that the B-cell differentiation are correlated with the L-asparaginase response in B-ALL. Further multiomics analysis confirmed that L-asparaginase resistant B-ALL had higher percentage of Pre-pro-B like cells and less Pro-B like cells. By targeting BCL2, the key hub genes in Pre-pro-B cell network, Venetoclax combined with L-asparaginase can produce better outcome as demonstrated by in vitro and in vivo evaluations. In conclusion, our results identified B-ALL heterogeneity in L-asparaginase-resistant signature and BCL2 signaling and B-cell maturation stage, consistent with L-asparaginase response, providing unique opportunities for total clonal therapy.
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| Overall design |
To check how the composition of B-cell development stage-like cells in B-ALL patients may indicate the drug response, we performed scMultiome profiling of two L-asparaginase sensitive (Ph-like_CRLF2, Near haploid) and two L-asparaginase resistant (KMT2A, Ph+) B-ALL cases. To further verify that L-asparaginase selectively kill the sensitive B cell population, we treated two L-asparaginase responsive B-ALL PDXs with L-asparaginase or vehicle ex vivo, followed by scMultiome analysis.
To further check how the composition of B-cell development stage-like cells change after venetoclax treatment, We treated an available PDX sample with L-asparaginase, venetoclax, or both, and then performed scRNA-seq analysis.
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| Contributor(s) |
Yang J, Yu J, Huang X, Li Y |
| Citation(s) |
38593781 |
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| Submission date |
Jun 26, 2023 |
| Last update date |
Apr 24, 2024 |
| Contact name |
Jun Yang |
| E-mail(s) |
jun.yang@stjude.org
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| Phone |
901-595-2517
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| Organization name |
St. Jude Children's Research Hospital
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| Department |
Pharmaceutical Sciences
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| Street address |
262 Danny Thomas Pl
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| City |
Memphis |
| State/province |
TN |
| ZIP/Postal code |
38105 |
| Country |
USA |
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| Platforms (1) |
| GPL24676 |
Illumina NovaSeq 6000 (Homo sapiens) |
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| Samples (20)
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| Relations |
| BioProject |
PRJNA987621 |
| Supplementary file |
Size |
Download |
File type/resource |
| GSE235787_RAW.tar |
20.5 Gb |
(http)(custom) |
TAR (of MTX, TSV) |
SRA Run Selector |
| Raw data are available in SRA |
| Processed data provided as supplementary file |
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