Annotation Detail
Information
- Associated Genes
- PRPS1
- Associated Variants
-
PRPS1 N144S
PRPS1 N144S - Associated Disease
- childhood B-cell acute lymphoblastic leukemia
- Source Database
- CIViC Evidence
- Description
- Lentiviral-mediated overexpression of PRPS1 N144S in Reh cells resulted in significant resistance against mercaptopurine (6-MP) and thioguanine (6-TG) as indicated by IC50 increases and reduced apoptosis compared to multiple controls (empty vector and overexpression of wildtype or known reduced-function PRPS1 mutants). 6-MP cytotoxicity results were confirmed using Jurkat cells. After 6-MP exposure, mass spectrometry revealed N144S cells possessed reduced concentrations of intracellular 6-MP metabolites (TIMP, TGMP, etc.) versus controls. N144S cells produce increased intracellular concentrations of hypoxanthine and IMP. Also, after 6-MP exposure, N144S cells display reduced levels of DNA damage response and apoptosis protein markers. The enhanced production of hypoxanthine likely leads to reduced conversion of thiopurines to their active form due to competitive inhibition.
- Variant Origin
- somatic
- Variant Origin
- Somatic
- Evidence URL
- https://civic.genome.wustl.edu/links/evidence_items/7903
- Gene URL
- https://civic.genome.wustl.edu/links/genes/4566
- Variant URL
- https://civic.genome.wustl.edu/links/variants/2923
- Rating
- 4
- Evidence Type
- Predictive
- Disease
- Childhood B-cell Acute Lymphoblastic Leukemia
- Evidence Direction
- Supports
- Drug
- Mercaptopurine,Thioguanine
- Evidence Level
- D
- Clinical Significance
- Resistance
- Pubmed
- 25962120
Drugs
| Drug Name | Sensitivity | Supported |
|---|---|---|
| Mercaptopurine | Resitance or Non-Reponse | true |
| Thioguanine | Resitance or Non-Reponse | true |