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| Status |
Public on Mar 29, 2014 |
| Title |
Therapeutic potential of spleen tyrosine kinase inhibition for treatment of high-risk precursor B-cell acute lymphoblastic leukemia |
| Organism |
Mus musculus |
| Experiment type |
Expression profiling by array
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| Summary |
This study revealed pathogenic role of pre-BCR-independent SYK activation in high-risk B-ALL.
Intensified and central nervous system (CNS)-directed chemotherapy has significantly improved outcomes for pediatric B-acute lymphoblastic leukemia (B-ALL), but confers significant late-effect morbidities. Moreover, many patients suffer relapses, underscoring the need to develop novel, molecularly targeted B-ALL therapies. Using a mouse model, we showed that leukemic B-cells require pre-B-cell receptor (pre-BCR)-independent spleen tyrosine kinase (SYK) signaling in vivo. In diagnostic samples from human B-ALL patients, SYK and downstream targets were phosphorylated regardless of pre-BCR expression or genetic subtype. Two small molecule SYK inhibitors, fostamatinib and BAY61-3606, attenuated growth of 69 B-ALL samples, including high-risk (HR) subtypes. Orally administered fostamatinib significantly reduced high disease burden after xenotransplantation of HR B-ALL samples into immune-deficient mice, and decreased leukemia dissemination into spleen, liver, kidneys and the CNS of recipients. Thus, SYK activation sustains growth of multiple HR B-ALL subtypes, suggesting that SYK inhibitors may improve outcomes for HR and relapsed B-ALL.
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| Overall design |
B-cell leukemia samples (3) from a mutant mouse model were compared to sorted or cultured preB or proB cells from normal mice using Affymetrix GeneChip arrays.
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| Contributor(s) |
Danska JS, Kowalski PE |
| Citation(s) |
24828076 |
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| Submission date |
Mar 28, 2014 |
| Last update date |
Feb 11, 2019 |
| Contact name |
Paul Kowalski |
| Organization name |
The Hospital for Sick Children
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| Department |
Developmental and Stem Cell Biology
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| Lab |
Cynthia Guidos
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| Street address |
PGCRL - 686 Bay St
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| City |
Toronto |
| State/province |
Ontario |
| ZIP/Postal code |
M5G 0A4 |
| Country |
Canada |
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| Platforms (1) |
| GPL1261 |
[Mouse430_2] Affymetrix Mouse Genome 430 2.0 Array |
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| Samples (9)
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| Relations |
| BioProject |
PRJNA242970 |
| Supplementary file |
Size |
Download |
File type/resource |
| GSE56345_RAW.tar |
35.5 Mb |
(http)(custom) |
TAR (of CEL, CHP) |
| Processed data included within Sample table |
| Processed data provided as supplementary file |
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