Annotation Detail
Information
- Associated Genes
- PRPS1
- Associated Variants
-
PRPS1 A190V
PRPS1 A190V - Associated Disease
- childhood B-cell acute lymphoblastic leukemia
- Source Database
- CIViC Evidence
- Description
- Lentiviral-mediated overexpression of PRPS1 A190T 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 A190T cells possessed reduced concentrations of intracellular 6-MP metabolites (TIMP, TGMP, etc.) versus controls. A190T cells produce increased intracellular concentrations of hypoxanthine and IMP. Also, after 6-MP exposure, A190T cells display reduced levels of DNA damage response and apoptosis protein markers. A190T results in the activation of the de novo purine synthesis pathway by reducing feedback inhibition, allowing the cell to continue to create nucleotides even when concentrations are elevated. This overactivation creates increased hypoxanthine levels, which likely competitively inhibits the conversion of the thiopurines to their active form.
- Variant Origin
- somatic
- Variant Origin
- Somatic
- Evidence URL
- https://civic.genome.wustl.edu/links/evidence_items/7909
- Gene URL
- https://civic.genome.wustl.edu/links/genes/4566
- Variant URL
- https://civic.genome.wustl.edu/links/variants/2929
- Rating
- 5
- Evidence Type
- Predictive
- Disease
- Childhood B-cell Acute Lymphoblastic Leukemia
- Evidence Direction
- Supports
- Drug
- Thioguanine,Mercaptopurine
- 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 |